{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T17:10:36Z","timestamp":1781111436380,"version":"3.54.1"},"reference-count":186,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Meiji Holdings Co., Ltd."},{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI from MEXT","doi-asserted-by":"publisher","award":["JP25K02271"],"award-info":[{"award-number":["JP25K02271"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cyclin-dependent kinase 5 (Cdk5) is an atypical serine\/threonine kinase distinct from classical cell cycle regulators. Its activity is highest in the nervous system and essential for development, but its functions in other tissues, particularly in cancer, are increasingly being elucidated. This review explores the functional duality of Cdk5 by comparing its constructive role in neurodevelopment with its repurposed oncogenic function in cancer. In neurodevelopment, Cdk5 orchestrates nearly every stage of brain construction, including neuronal differentiation, migration, and synaptic plasticity. However, in many cancers, this neurodevelopmental toolkit is repurposed, and aberrantly activated Cdk5 promotes proliferation, metastasis, and therapeutic resistance in diverse solid tumors. Cdk5 also actively shapes the tumor microenvironment by promoting angiogenesis and modulating immunity. Notably, this oncogenic function is not universal, as Cdk5 exhibits its duality even within the context of cancer; it acts as a tumor suppressor in gastric cancer upon nuclear localization. Taken together, these lines of evidence underscore that Cdk5 is a context-dependent kinase whose output is determined by upstream regulation, subcellular localization, and the cellular environment. This review discusses the molecular basis of its dual role and highlights both the potential and complexity of Cdk5 as a therapeutic target in oncology.<\/jats:p>","DOI":"10.3390\/cells14231876","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T10:25:16Z","timestamp":1764239116000},"page":"1876","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Duality of Cdk5: A Master Regulator in Neurodevelopment and a Hijacked Oncogene in Cancer"],"prefix":"10.3390","volume":"14","author":[{"given":"Yoshiaki V.","family":"Nishimura","sequence":"first","affiliation":[{"name":"Division of Neuroscience, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1 Fukumuro, Miyagino-ku, Sendai, Miyagi 983-8536, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8650-4474","authenticated-orcid":false,"given":"Takeshi","family":"Kawauchi","sequence":"additional","affiliation":[{"name":"Department of Adaptive and Maladaptive Responses in Health and Disease, Graduate School of Medicine, Kyoto University, Medical Innovation Center (3F), 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan"},{"name":"Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10867","DOI":"10.1073\/pnas.89.22.10867","article-title":"Neuronal cdc2-like kinase: A cdc2-related protein kinase with predominantly neuronal expression","volume":"89","author":"Hellmich","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"25922","DOI":"10.1016\/S0021-9258(18)35696-5","article-title":"Brain proline-directed protein kinase is a neurofilament kinase which displays high sequence homology to p34cdc2","volume":"267","author":"Lew","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2909","DOI":"10.1002\/j.1460-2075.1992.tb05360.x","article-title":"A family of human cdc2-related protein kinases","volume":"11","author":"Meyerson","year":"1992","journal-title":"EMBO J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/0092-8674(92)90518-H","article-title":"D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA","volume":"71","author":"Xiong","year":"1992","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1242\/dev.119.4.1029","article-title":"Activity and expression pattern of cyclin-dependent kinase 5 in the embryonic mouse nervous system","volume":"119","author":"Tsai","year":"1993","journal-title":"Development"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/371423a0","article-title":"A brain-specific activator of cyclin-dependent kinase 5","volume":"371","author":"Lew","year":"1994","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1038\/371419a0","article-title":"p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5","volume":"371","author":"Tsai","year":"1994","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/0014-5793(94)01163-X","article-title":"Precursor of cdk5 activator, the 23 kDa subunit of tau protein kinase II: Its sequence and developmental change in brain","volume":"355","author":"Uchida","year":"1994","journal-title":"FEBS Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"26897","DOI":"10.1074\/jbc.270.45.26897","article-title":"An isoform of the neuronal cyclin-dependent kinase 5 (Cdk5) activator","volume":"270","author":"Tang","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1242\/jcs.113.6.975","article-title":"p39 activates cdk5 in neurons, and is associated with the actin cytoskeleton","volume":"113","author":"Humbert","year":"2000","journal-title":"J. Cell Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6758","DOI":"10.1523\/JNEUROSCI.21-17-06758.2001","article-title":"p35 and p39 are essential for cyclin-dependent kinase 5 function during neurodevelopment","volume":"21","author":"Ko","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10506","DOI":"10.1074\/jbc.M211964200","article-title":"Tau phosphorylation by cyclin-dependent kinase 5\/p39 during brain development reduces its affinity for microtubules","volume":"278","author":"Takahashi","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Cheng, A., Wang, J., Li, J., Wang, J., Xu, M., Chen, H., and Zhang, P. (2024). S-Nitrosylation of p39 promotes its degradation and contributes to synaptic dysfunction induced by beta-amyloid peptide. Commun. Biol., 7.","DOI":"10.1038\/s42003-024-06832-z"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/45159","article-title":"Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration","volume":"402","author":"Patrick","year":"1999","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1111\/j.1471-4159.2008.05500.x","article-title":"Myristoylation of p39 and p35 is a determinant of cytoplasmic or nuclear localization of active cyclin-dependent kinase 5 complexes","volume":"106","author":"Asada","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1038\/s41593-019-0491-3","article-title":"Single-cell transcriptomic profiling of the aging mouse brain","volume":"22","author":"Ximerakis","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3089","DOI":"10.1172\/JCI37978","article-title":"Cyclin I activates Cdk5 and regulates expression of Bcl-2 and Bcl-XL in postmitotic mouse cells","volume":"119","author":"Brinkkoetter","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"F1161","DOI":"10.1152\/ajprenal.00614.2011","article-title":"Both cyclin I and p35 are required for maximal survival benefit of cyclin-dependent kinase 5 in kidney podocytes","volume":"302","author":"Taniguchi","year":"2012","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"C339","DOI":"10.1152\/ajpcell.00168.2014","article-title":"Cyclin I and p35 determine the subcellular distribution of Cdk5","volume":"308","author":"Hagmann","year":"2015","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Liu, C., Zhai, X., Zhao, B., Wang, Y., and Xu, Z. (2017). Cyclin I-like (CCNI2) is a cyclin-dependent kinase 5 (CDK5) activator and is involved in cell cycle regulation. Sci. Rep., 7.","DOI":"10.1038\/srep40979"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1038\/s41586-024-07888-x","article-title":"CDK5-cyclin B1 regulates mitotic fidelity","volume":"633","author":"Zheng","year":"2024","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.ccr.2013.08.027","article-title":"The role of Cdk5 in neuroendocrine thyroid cancer","volume":"24","author":"Pozo","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"24057","DOI":"10.1074\/jbc.273.37.24057","article-title":"p35, the neuronal-specific activator of cyclin-dependent kinase 5 (Cdk5) is degraded by the ubiquitin-proteasome pathway","volume":"273","author":"Patrick","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1007\/s12017-014-8336-4","article-title":"Sumoylation of p35 modulates p35\/cyclin-dependent kinase (Cdk) 5 complex activity","volume":"17","author":"Krumova","year":"2015","journal-title":"Neuromolecular Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8665","DOI":"10.1038\/ncomms9665","article-title":"S-nitrosylation-dependent proteasomal degradation restrains Cdk5 activity to regulate hippocampal synaptic strength","volume":"6","author":"Zhang","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"39014","DOI":"10.1074\/jbc.M512663200","article-title":"Identification of nuclear import mechanisms for the neuronal Cdk5 activator","volume":"281","author":"Fu","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Lee, J., Ko, Y.U., Chung, Y., Yun, N., Kim, M., Kim, K., and Oh, Y.J. (2018). The acetylation of cyclin-dependent kinase 5 at lysine 33 regulates kinase activity and neurite length in hippocampal neurons. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-31785-9"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"14366","DOI":"10.1523\/JNEUROSCI.3899-10.2010","article-title":"S-nitrosylation of cyclin-dependent kinase 5 (cdk5) regulates its kinase activity and dendrite growth during neuronal development","volume":"30","author":"Zhang","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/S0896-6273(02)00857-7","article-title":"Fyn and Cdk5 mediate semaphorin-3A signaling, which is involved in regulation of dendrite orientation in cerebral cortex","volume":"35","author":"Sasaki","year":"2002","journal-title":"Neuron"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"19627","DOI":"10.1074\/jbc.M113.501148","article-title":"Phosphorylation of cyclin-dependent kinase 5 (Cdk5) at Tyr-15 is inhibited by Cdk5 activators and does not contribute to the activation of Cdk5","volume":"289","author":"Kobayashi","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11156","DOI":"10.1073\/pnas.96.20.11156","article-title":"Regulation of cyclin-dependent kinase 5 catalytic activity by phosphorylation","volume":"96","author":"Sharma","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/S1097-2765(01)00343-4","article-title":"Structure and regulation of the CDK5-p25(nck5a) complex","volume":"8","author":"Tarricone","year":"2001","journal-title":"Mol. Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.devcel.2011.08.009","article-title":"Cyclin E constrains Cdk5 activity to regulate synaptic plasticity and memory formation","volume":"21","author":"Odajima","year":"2011","journal-title":"Dev. Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1111\/j.1471-4159.2011.07343.x","article-title":"Glutathione-S-transferase P1 is a critical regulator of Cdk5 kinase activity","volume":"118","author":"Sun","year":"2011","journal-title":"J. Neurochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1038\/s41388-018-0142-2","article-title":"Regulation of inside-out beta1-integrin activation by CDCP1","volume":"37","author":"Pollan","year":"2018","journal-title":"Oncogene"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/ncb1338","article-title":"Cdk5 phosphorylates and stabilizes p27kip1 contributing to actin organization and cortical neuronal migration","volume":"8","author":"Kawauchi","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.neuron.2013.06.017","article-title":"Axin directs the amplification and differentiation of intermediate progenitors in the developing cerebral cortex","volume":"79","author":"Fang","year":"2013","journal-title":"Neuron"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"13613","DOI":"10.1523\/JNEUROSCI.3120-11.2011","article-title":"Cdk5-mediated phosphorylation of Axin directs axon formation during cerebral cortex development","volume":"31","author":"Fang","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.neuron.2010.06.002","article-title":"Dixdc1 is a critical regulator of DISC1 and embryonic cortical development","volume":"67","author":"Singh","year":"2010","journal-title":"Neuron"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4826","DOI":"10.1038\/ncomms5826","article-title":"Cdk5-mediated phosphorylation of RapGEF2 controls neuronal migration in the developing cerebral cortex","volume":"5","author":"Ye","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1016\/j.neuron.2010.07.007","article-title":"Rab GTPases-dependent endocytic pathways regulate neuronal migration and maturation through N-cadherin trafficking","volume":"67","author":"Kawauchi","year":"2010","journal-title":"Neuron"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/S0960-9822(00)00411-5","article-title":"Regulation of N-cadherin-mediated adhesion by the p35-Cdk5 kinase","volume":"10","author":"Kwon","year":"2000","journal-title":"Curr. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S0896-6273(03)00852-3","article-title":"Cdk5 phosphorylation of doublecortin ser297 regulates its effect on neuronal migration","volume":"41","author":"Tanaka","year":"2004","journal-title":"Neuron"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/S0896-6273(00)00146-X","article-title":"A LIS1\/NUDEL\/cytoplasmic dynein heavy chain complex in the developing and adult nervous system","volume":"28","author":"Sasaki","year":"2000","journal-title":"Neuron"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Doobin, D.J., Helmer, P., Carabalona, A., Bertipaglia, C., and Vallee, R.B. (2024). The Role of Nde1 phosphorylation in interkinetic nuclear migration and neural migration during cortical development. Mol. Biol. Cell, 35.","DOI":"10.1091\/mbc.E24-05-0217"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1093\/cercor\/bhab228","article-title":"Requirement of CRMP2 Phosphorylation in Neuronal Migration of Developing Mouse Cerebral Cortex and Hippocampus and Redundant Roles of CRMP1 and CRMP4","volume":"32","author":"Yamazaki","year":"2022","journal-title":"Cereb. Cortex"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4957","DOI":"10.1074\/jbc.273.9.4957","article-title":"Regulation of Munc-18\/syntaxin 1A interaction by cyclin-dependent kinase 5 in nerve endings","volume":"273","author":"Shuang","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"8104","DOI":"10.1074\/jbc.M008932200","article-title":"Amphiphysin 1 binds the cyclin-dependent kinase (cdk) 5 regulatory subunit p35 and is phosphorylated by cdk5 and cdc2","volume":"276","author":"Floyd","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1083\/jcb.200308110","article-title":"Cophosphorylation of amphiphysin I and dynamin I by Cdk5 regulates clathrin-mediated endocytosis of synaptic vesicles","volume":"163","author":"Tomizawa","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/ncb1020","article-title":"Cdk5 is essential for synaptic vesicle endocytosis","volume":"5","author":"Tan","year":"2003","journal-title":"Nat. Cell Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e53659","DOI":"10.15252\/embr.202153659","article-title":"Bassoon controls synaptic vesicle release via regulation of presynaptic phosphorylation and cAMP","volume":"23","author":"Guhathakurta","year":"2022","journal-title":"EMBO Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.neuron.2012.06.023","article-title":"Regulation of N-type voltage-gated calcium channels and presynaptic function by cyclin-dependent kinase 5","volume":"75","author":"Su","year":"2012","journal-title":"Neuron"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2590","DOI":"10.1523\/JNEUROSCI.22-07-02590.2002","article-title":"Cdk5\/p35 regulates neurotransmitter release through phosphorylation and downregulation of P\/Q-type voltage-dependent calcium channel activity","volume":"22","author":"Tomizawa","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"12742","DOI":"10.1073\/pnas.211428098","article-title":"Regulation of NMDA receptors by cyclin-dependent kinase-5","volume":"98","author":"Li","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1523\/JNEUROSCI.1900-07.2008","article-title":"Cdk5 regulates the phosphorylation of tyrosine 1472 NR2B and the surface expression of NMDA receptors","volume":"28","author":"Zhang","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1016\/j.neuron.2014.01.022","article-title":"Memory enhancement by targeting Cdk5 regulation of NR2B","volume":"81","author":"Plattner","year":"2014","journal-title":"Neuron"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1007\/s12035-021-02581-w","article-title":"Phosphorylation of CRMP2 by Cdk5 Negatively Regulates the Surface Delivery and Synaptic Function of AMPA Receptors","volume":"59","author":"Cheng","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1523\/JNEUROSCI.4582-03.2004","article-title":"Cyclin-dependent kinase 5 phosphorylates the N-terminal domain of the postsynaptic density protein PSD-95 in neurons","volume":"24","author":"Morabito","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"7264","DOI":"10.1523\/JNEUROSCI.2309-22.2023","article-title":"Regulation of NLGN3 and the Synaptic Rho-GEF Signaling Pathway by CDK5","volume":"43","author":"Jeong","year":"2023","journal-title":"J. Neurosci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"ENEURO.0278-23.2025","DOI":"10.1523\/ENEURO.0278-23.2025","article-title":"Phosphorylation of NLGN4X Regulates Spinogenesis and Synaptic Function","volume":"12","author":"Lehr","year":"2025","journal-title":"eNeuro"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"9491","DOI":"10.1523\/JNEUROSCI.3209-18.2019","article-title":"The LMTK1-TBC1D9B-Rab11A Cascade Regulates Dendritic Spine Formation via Endosome Trafficking","volume":"39","author":"Nishino","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"36878","DOI":"10.1074\/jbc.M113.494856","article-title":"Cyclin-dependent kinase 5 (Cdk5) regulates the function of CLOCK protein by direct phosphorylation","volume":"288","author":"Kwak","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e50925","DOI":"10.7554\/eLife.50925","article-title":"Cyclin-dependent kinase 5 (CDK5) regulates the circadian clock","volume":"8","author":"Brenna","year":"2019","journal-title":"eLife"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/s41398-025-03551-9","article-title":"CDK5-mediated hyperphosphorylation of Tau217 impairs neuronal synaptic structure and exacerbates cognitive impairment in Alzheimer\u2019s disease","volume":"15","author":"Fu","year":"2025","journal-title":"Transl. Psychiatry"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"9658","DOI":"10.1523\/JNEUROSCI.1773-05.2005","article-title":"Cyclin-dependent kinase 5 is essential for neuronal cell cycle arrest and differentiation","volume":"25","author":"Cicero","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3601","DOI":"10.1091\/mbc.e10-01-0054","article-title":"Phosphorylation of p27Kip1 at Thr187 by cyclin-dependent kinase 5 modulates neural stem cell differentiation","volume":"21","author":"Zheng","year":"2010","journal-title":"Mol. Biol. Cell"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1101\/gad.377106","article-title":"p27kip1 independently promotes neuronal differentiation and migration in the cerebral cortex","volume":"20","author":"Nguyen","year":"2006","journal-title":"Genes. Dev."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1038\/192766b0","article-title":"Autoradiographic study of cell migration during histogenesis of cerebral cortex in the mouse","volume":"192","author":"Angevine","year":"1961","journal-title":"Nature"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"9996","DOI":"10.1523\/JNEUROSCI.23-31-09996.2003","article-title":"Multipolar migration: The third mode of radial neuronal migration in the developing cerebral cortex","volume":"23","author":"Tabata","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/83967","article-title":"Two modes of radial migration in early development of the cerebral cortex","volume":"4","author":"Nadarajah","year":"2001","journal-title":"Nat. Neurosci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1002\/cne.901450105","article-title":"Mode of cell migration to the superficial layers of fetal monkey neocortex","volume":"145","author":"Rakic","year":"1972","journal-title":"J. Comp. Neurol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"11173","DOI":"10.1073\/pnas.93.20.11173","article-title":"Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death","volume":"93","author":"Ohshima","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"6370","DOI":"10.1523\/JNEUROSCI.18-16-06370.1998","article-title":"Cyclin-dependent kinase 5-deficient mice demonstrate novel developmental arrest in cerebral cortex","volume":"18","author":"Gilmore","year":"1998","journal-title":"J. Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1002\/(SICI)1096-9861(19980615)395:4<510::AID-CNE7>3.0.CO;2-4","article-title":"A novel disruption of cortical development in p35(-\/-) mice distinct from reeler","volume":"395","author":"Kwon","year":"1998","journal-title":"J. Comp. Neurol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3540","DOI":"10.1242\/dev.111294","article-title":"Cdk5 and its substrates, Dcx and p27kip1, regulate cytoplasmic dilation formation and nuclear elongation in migrating neurons","volume":"141","author":"Nishimura","year":"2014","journal-title":"Development"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1016\/j.neuron.2023.01.020","article-title":"Centrosomal microtubule nucleation regulates radial migration of projection neurons independently of polarization in the developing brain","volume":"111","author":"Vinopal","year":"2023","journal-title":"Neuron"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/S0896-6273(00)00147-1","article-title":"NUDEL is a novel Cdk5 substrate that associates with LIS1 and cytoplasmic dynein","volume":"28","author":"Niethammer","year":"2000","journal-title":"Neuron"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S0896-6273(00)80777-1","article-title":"Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons","volume":"23","author":"Francis","year":"1999","journal-title":"Neuron"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/S0896-6273(00)80778-3","article-title":"Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons","volume":"23","author":"Gleeson","year":"1999","journal-title":"Neuron"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1093\/hmg\/8.9.1599","article-title":"Doublecortin, a stabilizer of microtubules","volume":"8","author":"Horesh","year":"1999","journal-title":"Hum. Mol. Genet."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.bbrc.2005.03.132","article-title":"MAP1B phosphorylation is differentially regulated by Cdk5\/p35, Cdk5\/p25, and JNK","volume":"331","author":"Kawauchi","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1038\/emboj.2008.182","article-title":"LIS1 and NDEL1 coordinate the plus-end-directed transport of cytoplasmic dynein","volume":"27","author":"Yamada","year":"2008","journal-title":"EMBO J."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1038\/nn1934","article-title":"Dual subcellular roles for LIS1 and dynein in radial neuronal migration in live brain tissue","volume":"10","author":"Tsai","year":"2007","journal-title":"Nat. Neurosci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.neuron.2005.04.013","article-title":"Nucleokinesis in neuronal migration","volume":"46","author":"Tsai","year":"2005","journal-title":"Neuron"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/ng1169","article-title":"14-3-3epsilon is important for neuronal migration by binding to NUDEL: A molecular explanation for Miller-Dieker syndrome","volume":"34","author":"Shionoya","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1016\/j.celrep.2017.08.024","article-title":"Folding of the Cerebral Cortex Requires Cdk5 in Upper-Layer Neurons in Gyrencephalic Mammals","volume":"20","author":"Shinmyo","year":"2017","journal-title":"Cell Rep."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2273","DOI":"10.1242\/dev.02854","article-title":"Cdk5 is required for multipolar-to-bipolar transition during radial neuronal migration and proper dendrite development of pyramidal neurons in the cerebral cortex","volume":"134","author":"Ohshima","year":"2007","journal-title":"Development"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1101\/gad.10.7.816","article-title":"The cdk5\/p35 kinase is essential for neurite outgrowth during neuronal differentiation","volume":"10","author":"Nikolic","year":"1996","journal-title":"Genes Dev."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1007\/s12035-024-04325-y","article-title":"CDK5 Deficiency Does not Impair Neuronal Differentiation of Human Induced Pluripotent Stem Cells but Affects Neurite Outgrowth","volume":"62","author":"Mucci","year":"2025","journal-title":"Mol. Neurobiol."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Desbois, M., Opperman, K.J., Amezquita, J., Gaglio, G., Crawley, O., and Grill, B. (2022). Ubiquitin ligase activity inhibits Cdk5 to control axon termination. PLoS Genet., 18.","DOI":"10.1371\/journal.pgen.1010152"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e109352","DOI":"10.15252\/embj.2021109352","article-title":"Endosomal phosphatidylinositol 3-phosphate controls synaptic vesicle cycling and neurotransmission","volume":"41","author":"Liu","year":"2022","journal-title":"EMBO J."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/s41398-024-03201-6","article-title":"Developmental deficits, synapse and dendritic abnormalities in a Clcn4 KO autism mice model: Endophenotypic target for ASD","volume":"15","author":"Lee","year":"2025","journal-title":"Transl. Psychiatry"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/s41398-024-02749-7","article-title":"Cdk5-dependent rapid formation and stabilization of dendritic spines by corticotropin-releasing factor","volume":"14","author":"Vandael","year":"2024","journal-title":"Transl. Psychiatry"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1111\/j.1471-4159.2005.03058.x","article-title":"Control of cyclin-dependent kinase 5 (Cdk5) activity by glutamatergic regulation of p35 stability","volume":"93","author":"Wei","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.neuroscience.2020.04.031","article-title":"Cyclin-dependent Kinase 5 Regulates Cortical Neurotransmission and Neural Circuits Associated with Motor Control in the Secondary Motor Cortex in the Mouse","volume":"438","author":"Li","year":"2020","journal-title":"Neuroscience"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"8054","DOI":"10.1074\/jbc.M109645200","article-title":"Calpain-mediated cleavage of the cyclin-dependent kinase-5 activator p39 to p29","volume":"277","author":"Patzke","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1038\/35012636","article-title":"Neurotoxicity induces cleavage of p35 to p25 by calpain","volume":"405","author":"Lee","year":"2000","journal-title":"Nature"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e97029","DOI":"10.7554\/eLife.97029","article-title":"Cyclin-dependent kinase 5 (Cdk5) activity is modulated by light and gates rapid phase shifts of the circadian clock","volume":"13","author":"Brenna","year":"2025","journal-title":"eLife"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0092-8674(00)81683-9","article-title":"The hallmarks of cancer","volume":"100","author":"Hanahan","year":"2000","journal-title":"Cell"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of Cancer: New Dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2776","DOI":"10.1074\/jbc.M607234200","article-title":"Cdk5 regulates STAT3 activation and cell proliferation in medullary thyroid carcinoma cells","volume":"282","author":"Lin","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"E975","DOI":"10.1152\/ajpendo.00615.2012","article-title":"Cyclin-dependent kinase 5 modulates STAT3 and androgen receptor activation through phosphorylation of Ser727 on STAT3 in prostate cancer cells","volume":"305","author":"Hsu","year":"2013","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1091\/mbc.E14-12-1634","article-title":"Cyclin-dependent kinase 5 acts as a critical determinant of AKT-dependent proliferation and regulates differential gene expression by the androgen receptor in prostate cancer cells","volume":"26","author":"Lindqvist","year":"2015","journal-title":"Mol. Biol. Cell"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"101054","DOI":"10.1016\/j.neo.2024.101054","article-title":"Prenatal p25-activated Cdk5 induces pituitary tumorigenesis through MCM2 phosphorylation-mediated cell proliferation","volume":"57","author":"Huang","year":"2024","journal-title":"Neoplasia"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"182","DOI":"10.3892\/mmr.2025.13547","article-title":"CDK5 targets p21(CIP1) to regulate thyroid cancer cell proliferation and malignancy in patients","volume":"32","author":"Tung","year":"2025","journal-title":"Mol. Med. Rep."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"3689","DOI":"10.1002\/cam4.3916","article-title":"CDK5 positively regulates Notch1 signaling in pancreatic cancer cells by phosphorylation","volume":"10","author":"Chu","year":"2021","journal-title":"Cancer Med."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e2415","DOI":"10.1038\/cddis.2016.333","article-title":"CDK5 functions as a tumor promoter in human colorectal cancer via modulating the ERK5-AP-1 axis","volume":"7","author":"Zhuang","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1186\/s12935-019-0952-5","article-title":"CDK5 neutralizes the tumor suppressing effect of BIN1 via mediating phosphorylation of c-MYC at Ser-62 site in NSCLC","volume":"19","author":"Zhang","year":"2019","journal-title":"Cancer Cell Int."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.jhep.2015.01.031","article-title":"Targeting cyclin dependent kinase 5 in hepatocellular carcinoma\u2014A novel therapeutic approach","volume":"63","author":"Ehrlich","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/ncb1829","article-title":"Phosphorylation of ATM by Cdk5 mediates DNA damage signalling and regulates neuronal death","volume":"11","author":"Tian","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"3066","DOI":"10.1080\/15384101.2015.1078020","article-title":"Cdk5 promotes DNA replication stress checkpoint activation through RPA-32 phosphorylation, and impacts on metastasis free survival in breast cancer patients","volume":"14","author":"Chiker","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_113","first-page":"4533","article-title":"Cyclin I promotes cisplatin resistance via Cdk5 activation in cervical cancer","volume":"19","author":"Li","year":"2015","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.molcel.2010.11.035","article-title":"The proapoptotic function of Noxa in human leukemia cells is regulated by the kinase Cdk5 and by glucose","volume":"40","author":"Lowman","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"27108","DOI":"10.18632\/oncotarget.8342","article-title":"Cyclin-dependent kinase 5 stabilizes hypoxia-inducible factor-1alpha: A novel approach for inhibiting angiogenesis in hepatocellular carcinoma","volume":"7","author":"Herzog","year":"2016","journal-title":"Oncotarget"},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Liang, Q., Li, L., Zhang, J., Lei, Y., Wang, L., Liu, D.X., Feng, J., Hou, P., Yao, R., and Zhang, Y. (2013). CDK5 is essential for TGF-beta1-induced epithelial-mesenchymal transition and breast cancer progression. Sci. Rep., 3.","DOI":"10.1038\/srep02932"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1038\/ncb1868","article-title":"Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration","volume":"11","author":"Huang","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"796","DOI":"10.21037\/tcr-24-1283","article-title":"Talin1 Ser425 phosphorylation promotes colorectal cancer progression and metastasis","volume":"14","author":"He","year":"2025","journal-title":"Transl. Cancer Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"8001","DOI":"10.1073\/pnas.1912617117","article-title":"Targeting the cyclin-dependent kinase 5 in metastatic melanoma","volume":"117","author":"Sharma","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1083\/jcb.201405105","article-title":"CDK5 is a major regulator of the tumor suppressor DLC1","volume":"207","author":"Tripathi","year":"2014","journal-title":"J. Cell Biol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1016\/j.apsb.2024.12.019","article-title":"CDK5-triggered G6PD phosphorylation at threonine 91 facilitating redox homeostasis reveals a vulnerability in breast cancer","volume":"15","author":"Bei","year":"2025","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1038\/s41418-024-01342-1","article-title":"Ubiquitin-specific protease 1 facilitates hepatocellular carcinoma progression by modulating mitochondrial fission and metabolic reprogramming via cyclin-dependent kinase 5 stabilization","volume":"31","author":"Bian","year":"2024","journal-title":"Cell Death Differ."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1016\/j.jpha.2023.06.005","article-title":"Histone deacetylase inhibitor pracinostat suppresses colorectal cancer by inducing CDK5-Drp1 signaling-mediated peripheral mitofission","volume":"13","author":"Liang","year":"2023","journal-title":"J. Pharm. Anal."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.1038\/s41388-022-02237-6","article-title":"O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation","volume":"41","author":"Ciraku","year":"2022","journal-title":"Oncogene"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1038\/s41556-024-01509-5","article-title":"Astrocyte-induced Cdk5 expedites breast cancer brain metastasis by suppressing MHC-I expression to evade immune recognition","volume":"26","author":"Yuzhalin","year":"2024","journal-title":"Nat. Cell Biol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"e007529","DOI":"10.1136\/jitc-2023-007529","article-title":"CDK5 destabilizes PD-L1 via chaperon-mediated autophagy to control cancer immune surveillance in hepatocellular carcinoma","volume":"11","author":"Zhang","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"101148","DOI":"10.1016\/j.tranon.2021.101148","article-title":"Knockdown of CDK5 down-regulates PD-L1 via the ubiquitination-proteasome pathway and improves antitumor immunity in lung adenocarcinoma","volume":"14","author":"Gao","year":"2021","journal-title":"Transl. Oncol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1046\/j.1471-4159.2002.00824.x","article-title":"Cdk5 phosphorylates p53 and regulates its activity","volume":"81","author":"Zhang","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/j.neuron.2008.10.015","article-title":"Deregulation of HDAC1 by p25\/Cdk5 in neurotoxicity","volume":"60","author":"Kim","year":"2008","journal-title":"Neuron"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1159\/000335158","article-title":"Cdk5 phosphorylates a component of the HDAC complex and regulates histone acetylation during neuronal cell death","volume":"21","author":"Fu","year":"2013","journal-title":"Neurosignals"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.bbrc.2011.04.115","article-title":"Phosphorylation of human DNMT1: Implication of cyclin-dependent kinases","volume":"409","author":"Lavoie","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"543","DOI":"10.21873\/anticanres.16842","article-title":"p35\/CDK5 Regulates Bladder Cancer Proliferation and Migration and Promotes Higher Tumor Grade and Poor Survival Rate in Patients with Bladder Cancer","volume":"44","author":"Oner","year":"2024","journal-title":"Anticancer. Res."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"3958","DOI":"10.7150\/jca.53981","article-title":"CDK5 Knockdown inhibits proliferation and induces apoptosis and Cell Cycle Arrest in Human Glioblastoma","volume":"12","author":"Zhou","year":"2021","journal-title":"J. Cancer"},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Kao, W.H., Chiu, K.Y., Tsai, S.C., Teng, C.J., Oner, M., Lai, C.H., Hsieh, J.T., Lin, C.C., Wang, H.Y., and Chen, M.C. (2025). PI3K\/Akt inhibition promotes AR activity and prostate cancer cell proliferation through p35-CDK5 modulation. Biochim. Biophys. Acta Mol. Basis Dis., 1871.","DOI":"10.1016\/j.bbadis.2024.167568"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"4573","DOI":"10.1093\/hmg\/ddv188","article-title":"CDK5 phosphorylates DRP1 and drives mitochondrial defects in NMDA-induced neuronal death","volume":"24","author":"Huang","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/s41389-021-00372-5","article-title":"Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors","volume":"10","author":"Carter","year":"2021","journal-title":"Oncogenesis"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.cell.2006.11.001","article-title":"Cancer metastasis: Building a framework","volume":"127","author":"Gupta","year":"2006","journal-title":"Cell"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1126\/science.1203543","article-title":"A perspective on cancer cell metastasis","volume":"331","author":"Chaffer","year":"2011","journal-title":"Science"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.cell.2016.11.037","article-title":"Emerging Biological Principles of Metastasis","volume":"168","author":"Lambert","year":"2017","journal-title":"Cell"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"E4874","DOI":"10.1073\/pnas.1514157112","article-title":"Cyclin-dependent kinase 5 activates guanine nucleotide exchange factor GIV\/Girdin to orchestrate migration-proliferation dichotomy","volume":"112","author":"Bhandari","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"8109","DOI":"10.1523\/JNEUROSCI.1130-11.2011","article-title":"Girdin is an intrinsic regulator of neuroblast chain migration in the rostral migratory stream of the postnatal brain","volume":"31","author":"Wang","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"E2955","DOI":"10.1073\/pnas.1516321113","article-title":"PDK1-Akt pathway regulates radial neuronal migration and microtubules in the developing mouse neocortex","volume":"113","author":"Itoh","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1038\/nrc822","article-title":"Epithelial-mesenchymal transitions in tumour progression","volume":"2","author":"Thiery","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"4564","DOI":"10.3390\/ijms13044564","article-title":"Cell adhesion and its endocytic regulation in cell migration during neural development and cancer metastasis","volume":"13","author":"Kawauchi","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/S0092-8674(03)00605-6","article-title":"Serine 732 phosphorylation of FAK by Cdk5 is important for microtubule organization, nuclear movement, and neuronal migration","volume":"114","author":"Xie","year":"2003","journal-title":"Cell"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.1038\/s44321-024-00138-7","article-title":"ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer","volume":"16","author":"Pozzato","year":"2024","journal-title":"EMBO Mol. Med."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1002\/jcb.10762","article-title":"Angiostatin-induced inhibition of endothelial cell proliferation\/apoptosis is associated with the down-regulation of cell cycle regulatory protein cdk5","volume":"91","author":"Sharma","year":"2004","journal-title":"J. Cell Biochem."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"35932","DOI":"10.1074\/jbc.M110.126177","article-title":"Cyclin-dependent kinase 5 regulates endothelial cell migration and angiogenesis","volume":"285","author":"Liebl","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1002\/jcp.24234","article-title":"Osteosarcoma cells induce endothelial cell proliferation during neo-angiogenesis","volume":"228","author":"Mancini","year":"2013","journal-title":"J. Cell Physiol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"6088","DOI":"10.18632\/oncotarget.6842","article-title":"Inhibition of endothelial Cdk5 reduces tumor growth by promoting non-productive angiogenesis","volume":"7","author":"Merk","year":"2016","journal-title":"Oncotarget"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1126\/science.aae0477","article-title":"Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor immunity","volume":"353","author":"Dorand","year":"2016","journal-title":"Science"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1038\/s41571-021-00546-5","article-title":"Clinical and therapeutic relevance of cancer-associated fibroblasts","volume":"18","author":"Chen","year":"2021","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s12943-018-0758-4","article-title":"Paracrine and epigenetic control of CAF-induced metastasis: The role of HOTAIR stimulated by TGF-ss1 secretion","volume":"17","author":"Ren","year":"2018","journal-title":"Mol. Cancer"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"6235","DOI":"10.1093\/nar\/gks240","article-title":"The CDK5 repressor CDK5RAP1 is a methylthiotransferase acting on nuclear and mitochondrial RNA","volume":"40","author":"Reiter","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.molimm.2015.06.015","article-title":"Cyclin-dependent kinase 5 represses Foxp3 gene expression and Treg development through specific phosphorylation of Stat3 at Serine 727","volume":"67","author":"Lam","year":"2015","journal-title":"Mol. Immunol."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.4161\/15384101.2014.987621","article-title":"Cdk5 controls IL-2 gene expression via repression of the mSin3a-HDAC complex","volume":"14","author":"Lam","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1073\/pnas.1011275108","article-title":"Phosphorylation of glutamyl-prolyl tRNA synthetase by cyclin-dependent kinase 5 dictates transcript-selective translational control","volume":"108","author":"Arif","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"7274","DOI":"10.1038\/ncomms8274","article-title":"Cdk5 controls lymphatic vessel development and function by phosphorylation of Foxc2","volume":"6","author":"Liebl","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1042\/BST0370483","article-title":"The DNA-damage response: New molecular insights and new approaches to cancer therapy","volume":"37","author":"Jackson","year":"2009","journal-title":"Biochem. Soc. Trans."},{"key":"ref_160","doi-asserted-by":"crossref","unstructured":"Yue, C.H., Oner, M., Chiu, C.Y., Chen, M.C., Teng, C.L., Wang, H.Y., Hsieh, J.T., Lai, C.H., and Lin, H. (2021). RET Regulates Human Medullary Thyroid Cancer Cell Proliferation through CDK5 and STAT3 Activation. Biomolecules, 11.","DOI":"10.3390\/biom11060860"},{"key":"ref_161","doi-asserted-by":"crossref","unstructured":"Yu, H.P., Xie, J.M., Li, B., Sun, Y.H., Gao, Q.G., Ding, Z.H., Wu, H.R., and Qin, Z.H. (2015). TIGAR regulates DNA damage and repair through pentosephosphate pathway and Cdk5-ATM pathway. Sci. Rep., 5.","DOI":"10.1038\/srep09853"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1158\/0008-5472.CAN-07-5115","article-title":"The EGFR-STAT3 oncogenic pathway up-regulates the Eme1 endonuclease to reduce DNA damage after topoisomerase I inhibition","volume":"68","author":"Vigneron","year":"2008","journal-title":"Cancer Res."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"26765","DOI":"10.1074\/jbc.M109.092304","article-title":"The cdk5 kinase regulates the STAT3 transcription factor to prevent DNA damage upon topoisomerase I inhibition","volume":"285","author":"Courapied","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"ra49","DOI":"10.1126\/scisignal.2002032","article-title":"A cell-based high-content screening assay reveals activators and inhibitors of cancer cell invasion","volume":"4","author":"Quintavalle","year":"2011","journal-title":"Sci. Signal."},{"key":"ref_165","doi-asserted-by":"crossref","unstructured":"Zhang, S., Lu, Z., Mao, W., Ahmed, A.A., Yang, H., Zhou, J., Jennings, N., Rodriguez-Aguayo, C., Lopez-Berestein, G., and Miranda, R. (2015). CDK5 Regulates Paclitaxel Sensitivity in Ovarian Cancer Cells by Modulating AKT Activation, p21Cip1- and p27Kip1-Mediated G1 Cell Cycle Arrest and Apoptosis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0131833"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"8315","DOI":"10.1073\/pnas.0408974102","article-title":"Microtubule-associated protein tau: A marker of paclitaxel sensitivity in breast cancer","volume":"102","author":"Rouzier","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1038\/sj.bjc.6603182","article-title":"Reduced tau expression in gastric cancer can identify candidates for successful Paclitaxel treatment","volume":"94","author":"Mimori","year":"2006","journal-title":"Br. J. Cancer"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1634\/stemcells.2008-0234","article-title":"Neurogenesis in the dentate gyrus depends on ciliary neurotrophic factor and signal transducer and activator of transcription 3 signaling","volume":"27","author":"Muller","year":"2009","journal-title":"Stem Cells"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1523\/JNEUROSCI.2875-05.2006","article-title":"Calpain-regulated p35\/cdk5 plays a central role in dopaminergic neuron death through modulation of the transcription factor myocyte enhancer factor 2","volume":"26","author":"Smith","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/nrg3354","article-title":"DNA methylation: Roles in mammalian development","volume":"14","author":"Smith","year":"2013","journal-title":"Nat. Rev. Genet."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/npp.2012.112","article-title":"DNA methylation and its basic function","volume":"38","author":"Moore","year":"2013","journal-title":"Neuropsychopharmacology"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1158\/1078-0432.CCR-14-1950","article-title":"Cyclin-dependent kinase 5 decreases in gastric cancer and its nuclear accumulation suppresses gastric tumorigenesis","volume":"21","author":"Cao","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.7150\/jca.14778","article-title":"Low Expression of CDK5 and p27 Are Associated with Poor Prognosis in Patients with Gastric Cancer","volume":"7","author":"Sun","year":"2016","journal-title":"J. Cancer"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"14052","DOI":"10.1074\/jbc.M109.068262","article-title":"Cdk5 nuclear localization is p27-dependent in nerve cells: Implications for cell cycle suppression and caspase-3 activation","volume":"285","author":"Zhang","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1186\/s12935-023-03112-4","article-title":"CDK5 promotes apoptosis and attenuates chemoresistance in gastric cancer via E2F1 signaling","volume":"23","author":"Cao","year":"2023","journal-title":"Cancer Cell Int."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1269\/jrr.08024","article-title":"Enhancement of radiosensitivity by roscovitine pretreatment in human non-small cell lung cancer A549 cells","volume":"49","author":"Zhang","year":"2008","journal-title":"J. Radiat. Res."},{"key":"ref_177","doi-asserted-by":"crossref","unstructured":"Rossini, E., Tamburello, M., Abate, A., Zini, S., Ribaudo, G., Gianoncelli, A., Calza, S., Valcamonico, F., Suardi, N.R., and Mirabella, G. (2024). The CDK Inhibitor Dinaciclib Improves Cisplatin Response in Nonseminomatous Testicular Cancer: A Preclinical Study. Cells, 13.","DOI":"10.3390\/cells13050368"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1097\/CAD.0000000000001545","article-title":"Dinaciclib exerts a tumor-suppressing effect via beta-catenin\/YAP axis in pancreatic ductal adenocarcinoma","volume":"35","author":"Li","year":"2024","journal-title":"Anticancer. Drugs"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"5100","DOI":"10.1158\/1078-0432.CCR-15-0313","article-title":"Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma","volume":"21","author":"Dolman","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"5216","DOI":"10.18632\/oncotarget.23749","article-title":"Characterization of CDK(5) inhibitor, 20-223 (aka CP668863) for colorectal cancer therapy","volume":"9","author":"Robb","year":"2018","journal-title":"Oncotarget"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1523\/JNEUROSCI.3593-12.2013","article-title":"Specific inhibition of p25\/Cdk5 activity by the Cdk5 inhibitory peptide reduces neurodegeneration in vivo","volume":"33","author":"Sundaram","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"335","DOI":"10.3233\/JAD-160916","article-title":"TFP5, a Peptide Inhibitor of Aberrant and Hyperactive Cdk5\/p25, Attenuates Pathological Phenotypes and Restores Synaptic Function in CK-p25Tg Mice","volume":"56","author":"Shukla","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"3221","DOI":"10.1091\/mbc.E15-12-0857","article-title":"The interaction of Munc 18 (p67) with the p10 domain of p35 protects in vivo Cdk5\/p35 activity from inhibition by TFP5, a peptide derived from p35","volume":"27","author":"Amin","year":"2016","journal-title":"Mol. Biol. Cell"},{"key":"ref_184","doi-asserted-by":"crossref","unstructured":"Tabouret, E., Wang, H., Amin, N., Jung, J., Appay, R., Cui, J., Song, Q., Cardone, A., Park, D.M., and Gilbert, M.R. (2020). TP5, a Peptide Inhibitor of Aberrant and Hyperactive CDK5\/p25: A Novel Therapeutic Approach against Glioblastoma. Cancers, 12.","DOI":"10.3390\/cancers12071935"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"8554","DOI":"10.1073\/pnas.141230798","article-title":"Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation","volume":"98","author":"Sakamoto","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.pharmthera.2017.02.027","article-title":"Targeted protein degradation by PROTACs","volume":"174","author":"Neklesa","year":"2017","journal-title":"Pharmacol. Ther."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/23\/1876\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T12:51:09Z","timestamp":1764679869000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/23\/1876"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,27]]},"references-count":186,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["cells14231876"],"URL":"https:\/\/doi.org\/10.3390\/cells14231876","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,27]]}}}