{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:10:03Z","timestamp":1787314203979,"version":"build-2736575974"},"reference-count":97,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T00:00:00Z","timestamp":1630022400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>To investigate the biological role of protein phosphorylation in human nonfunctional pituitary neuroendocrine tumors (NF-PitNETs), proteins extracted from NF-PitNET and control tissues were analyzed with tandem mass tag (TMT)-based quantitative proteomics coupled with TiO2 enrichment of phosphopeptides. A total of 595 differentially phosphorylated proteins (DPPs) with 1412 phosphosites were identified in NF-PitNETs compared to controls (p &lt; 0.05). KEGG pathway network analysis of 595 DPPs identified nine statistically significant signaling pathways, including the spliceosome pathway, the RNA transport pathway, proteoglycans in cancer, SNARE interactions in vesicular transport, platelet activation, bacterial invasion of epithelial cells, tight junctions, vascular smooth muscle contraction, and protein processing in the endoplasmic reticulum. GO analysis revealed that these DPPs were involved in multiple cellular components (CCs), biological processes (BPs), and molecule functions (MFs). The kinase analysis of 595 DPPs identified seven kinases, including GRP78, WSTF, PKN2, PRP4, LOK, NEK1, and AMPKA1, and the substrate of these kinases could provide new ideas for seeking drug targets for NF-PitNETs. The randomly selected DPP calnexin was further confirmed with immunoprecipitation (IP) and Western blot (WB). These findings provide the first DPP profiling, phosphorylation-mediated molecular network alterations, and the key kinase profiling in NF-PitNET pathogenesis, which are a precious resource for understanding the biological roles of protein phosphorylation in NF-PitNET pathogenesis and discovering effective phosphoprotein biomarkers and therapeutic targets and drugs for the management of NF-PitNETs.<\/jats:p>","DOI":"10.3390\/cells10092225","type":"journal-article","created":{"date-parts":[[2021,8,29]],"date-time":"2021-08-29T21:45:16Z","timestamp":1630273516000},"page":"2225","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Phosphorylation-Mediated Molecular Pathway Changes in Human Pituitary Neuroendocrine Tumors Identified by Quantitative Phosphoproteomics"],"prefix":"10.3390","volume":"10","author":[{"given":"Jiajia","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Central South University, 87 Xiangya Road, Changsha 410008, China"},{"name":"Medical Science and Technology Innovation Center, Shandong First Medical University, 6699 Qingdao Road, Jinan 250117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Wen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Central South University, 87 Xiangya Road, Changsha 410008, China"},{"name":"Medical Science and Technology Innovation Center, Shandong First Medical University, 6699 Qingdao Road, Jinan 250117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biao","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Central South University, 87 Xiangya Road, Changsha 410008, China"},{"name":"Medical Science and Technology Innovation Center, Shandong First Medical University, 6699 Qingdao Road, Jinan 250117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Li","sequence":"additional","affiliation":[{"name":"Medical Science and Technology Innovation Center, Shandong First Medical University, 6699 Qingdao Road, Jinan 250117, China"},{"name":"Shandong Key Laboratory of Radiation Oncology, Shandong First Medical University, 440 Jiyan Road, Jinan 250117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianquan","family":"Zhan","sequence":"additional","affiliation":[{"name":"Medical Science and Technology Innovation Center, Shandong First Medical University, 6699 Qingdao Road, Jinan 250117, China"},{"name":"Shandong Key Laboratory of Radiation Oncology, Shandong First Medical University, 440 Jiyan Road, Jinan 250117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/35057062","article-title":"Initial sequencing and analysis of the human genome","volume":"409","author":"Lander","year":"2001","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s13167-010-0028-z","article-title":"The use of variations in proteomes to predict, prevent, and personalize treatment for clinically nonfunctional pituitary adenomas","volume":"1","author":"Zhan","year":"2010","journal-title":"EPMA J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1002\/mas.20039","article-title":"Comparative proteomics analysis of human pituitary adenomas: Current status and future perspectives","volume":"24","author":"Zhan","year":"2005","journal-title":"Mass Spectrom. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1002\/elps.201700330","article-title":"How many proteins can be identified in a 2DE gel spot within an analysis of a complex human cancer tissue proteome?","volume":"39","author":"Zhan","year":"2018","journal-title":"Electrophoresis"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1002\/prot.25388","article-title":"Prediction of phosphorylation sites based on Krawtchouk image moments","volume":"85","author":"Wang","year":"2017","journal-title":"Proteins"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.bioorg.2011.07.004","article-title":"Protein kinase biochemistry and drug discovery","volume":"39","author":"Schwartz","year":"2011","journal-title":"Bioorg. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"270","DOI":"10.3389\/fgene.2014.00270","article-title":"Physicochemical mechanisms of protein regulation by phosphorylation","volume":"5","author":"Nishi","year":"2014","journal-title":"Front. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1038\/sj.bjc.6602862","article-title":"Elevated phosphorylation and activation of PDK-1\/AKT pathway in human breast cancer","volume":"93","author":"Lin","year":"2005","journal-title":"Br. J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"50883","DOI":"10.18632\/oncotarget.10550","article-title":"Phosphorylation of kinase insert domain receptor by cyclin-dependent kinase 5 at serine 229 is associated with invasive behavior and poor prognosis in prolactin pituitary adenomas","volume":"7","author":"Xie","year":"2016","journal-title":"Oncotarget"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"86","DOI":"10.3389\/fendo.2016.00086","article-title":"Editorial: Systems Biological Aspects of Pituitary Tumors","volume":"7","author":"Zhan","year":"2016","journal-title":"Front. Endocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1186\/s12967-019-1915-2","article-title":"Predicting the regrowth of clinically non-functioning pituitary adenoma with a statistical model","volume":"17","author":"Cheng","year":"2019","journal-title":"J. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Yamanaka, R., Abe, E., Sato, T., Hayano, A., and Takashima, Y. (2017). Secondary Intracranial Tumors Following Radiotherapy for Pituitary Adenomas: A Systematic Review. Cancers, 9.","DOI":"10.3390\/cancers9080103"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1038\/cr.2016.114","article-title":"The genome-wide mutational landscape of pituitary adenomas","volume":"26","author":"Song","year":"2016","journal-title":"Cell Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2432","DOI":"10.1158\/1541-7786.MCR-19-0434","article-title":"Genetic and epigenetic characterization of growth hormone-secreting pituitary tumors","volume":"17","author":"Karppinen","year":"2019","journal-title":"Mol. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"M73","DOI":"10.1530\/EJE-15-0320","article-title":"Decoding the genetic basis of Cushing\u2019s disease: USP8 in the spotlight","volume":"173","author":"Theodoropoulou","year":"2015","journal-title":"Eur. J. Endocrinol."},{"key":"ref_16","first-page":"4585","article-title":"Genome-wide analysis of differentially expressed lncRNAs and mRNAs in primary gonadotrophin adenomas by RNA-seq","volume":"8","author":"Li","year":"2017","journal-title":"Oncotarget"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/nrm2203","article-title":"Mechanisms of specificity in protein phosphorylation","volume":"8","author":"Ubersax","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1126\/science.1075762","article-title":"The protein kinase complement of the human genome","volume":"298","author":"Manning","year":"2002","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1093\/jb\/mvy115","article-title":"Comprehensive analysis of kinase-oriented phospho-signalling pathways","volume":"165","author":"Amano","year":"2019","journal-title":"J. Biochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7469","DOI":"10.1021\/ac301572t","article-title":"Increasing the multiplexing capacity of TMTs using reporter ion isotopologues with isobaric masses","volume":"84","author":"McAlister","year":"2012","journal-title":"Anal. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/978-1-4939-0685-7_12","article-title":"Employing TMT Quantification in a Shotgun-MS Platform","volume":"Volume 1156","author":"Martins","year":"2014","journal-title":"Shotgun Proteomics: Methods and Protocols"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.jpba.2015.04.013","article-title":"Stable isotope labelling methods in mass spectrometry-based quantitative proteomics","volume":"113","author":"Chahrour","year":"2015","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1038\/nm.4165","article-title":"Therapeutic targeting of splicing in cancer","volume":"22","author":"Lee","year":"2016","journal-title":"Nat. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1080\/0968768031000122548","article-title":"ER-to-Golgi transport: COP I and COP II function (Review)","volume":"20","author":"Duden","year":"2003","journal-title":"Mol. Membr. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1080\/15548627.2017.1287657","article-title":"Autophagosome formation: Where the secretory and autophagy pathways meet","volume":"13","author":"Wang","year":"2017","journal-title":"Autophagy"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"25659","DOI":"10.1073\/pnas.1902909116","article-title":"Mechanisms of noncanonical binding dynamics in multivalent protein-protein interactions","volume":"116","author":"Errington","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1016\/j.cell.2011.11.016","article-title":"Cancer invasion and the microenvironment: Plasticity and reciprocity","volume":"147","author":"Friedl","year":"2011","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/nrc.2017.99","article-title":"Non-coding RNA networks in cancer","volume":"18","author":"Anastasiadou","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1007\/s11427-013-4575-0","article-title":"Spectrin: Structure, function and disease","volume":"56","author":"Zhang","year":"2013","journal-title":"Sci. China Life Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"a026930","DOI":"10.1101\/cshperspect.a026930","article-title":"The Many Roles of BAF (mSWI\/SNF) and PBAF Complexes in Cancer","volume":"6","author":"Hodges","year":"2016","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1016\/j.cell.2018.09.032","article-title":"Modular Organization and Assembly of SWI\/SNF Family Chromatin Remodeling Complexes","volume":"175","author":"Mashtalir","year":"2018","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1093\/neuonc\/noaa004","article-title":"SWI\/SNF complex heterogeneity is related to polyphenotypic differentiation, prognosis, and immune response in rhabdoid tumors","volume":"22","author":"Panwalkar","year":"2020","journal-title":"Neuro Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1038\/ng.2798","article-title":"Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation","volume":"45","author":"Guo","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5","DOI":"10.3389\/fphys.2017.00005","article-title":"The Multifaceted Role of SNARE Proteins in Membrane Fusion","volume":"8","author":"Han","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1146\/annurev-biophys-060414-033841","article-title":"Regulation of Rad6\/Rad18 Activity during DNA Damage Tolerance","volume":"44","author":"Hedglin","year":"2015","journal-title":"Annu. Rev. Biophys."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/s41594-020-0380-1","article-title":"FANCD2-FANCI is a clamp stabilized on DNA by monoubiquitination of FANCD2 during DNA repair","volume":"27","author":"Shakeel","year":"2020","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kim, H.J. (2019). Cell Fate Control by Translation: mRNA Translation Initiation as a Therapeutic Target for Cancer Development and Stem Cell Fate Control. Biomolecules, 9.","DOI":"10.3390\/biom9110665"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e45947","DOI":"10.15252\/embr.201845947","article-title":"Translation acrobatics: How cancer cells exploit alternate modes of translational initiation","volume":"19","author":"Sriram","year":"2018","journal-title":"EMBO Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.ceb.2019.02.006","article-title":"Chromatin\u2019s physical properties shape the nucleus and its functions","volume":"58","author":"Stephens","year":"2019","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.molcel.2019.04.034","article-title":"Co-transcriptional Loading of RNA Export Factors Shapes the Human Transcriptome","volume":"75","author":"Viphakone","year":"2019","journal-title":"Mol. Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3904","DOI":"10.1111\/j.1742-4658.2010.07800.x","article-title":"Proteoglycans in health and disease: Novel roles for proteoglycans in malignancy and their pharmacological targeting","volume":"277","author":"Theocharis","year":"2010","journal-title":"FEBS J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.biocel.2016.09.009","article-title":"CD44: More than a mere stem cell marker","volume":"81","author":"Morath","year":"2016","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/35052017","article-title":"SNARE-mediated membrane fusion","volume":"2","author":"Chen","year":"2001","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1146\/annurev-food-030212-182700","article-title":"The secretion, components, and properties of saliva","volume":"4","author":"Carpenter","year":"2013","journal-title":"Annu. Rev. Food Sci. Technol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.1161\/ATVBAHA.110.207522","article-title":"Signaling during platelet adhesion and activation","volume":"30","author":"Li","year":"2010","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1182\/blood-2017-06-742676","article-title":"Platelets and vascular integrity: How platelets prevent bleeding in inflammation","volume":"131","author":"Boulaftali","year":"2018","journal-title":"Blood"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.chom.2007.10.001","article-title":"Invasive and adherent bacterial pathogens co-Opt host clathrin for infection","volume":"2","author":"Veiga","year":"2007","journal-title":"Cell Host Microbe"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1111\/j.1365-2818.2008.02065.x","article-title":"Non-classical use of clathrin during bacterial infections","volume":"231","author":"Cossart","year":"2008","journal-title":"J. Microsc."},{"key":"ref_49","first-page":"1145","article-title":"Role of tight junctions in signal transduction: An update","volume":"13","author":"Takano","year":"2014","journal-title":"EXCLI J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.semcdb.2014.08.009","article-title":"Tight junctions and the regulation of gene expression","volume":"36","year":"2014","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.autneu.2017.07.007","article-title":"Imaging sympathetic neurogenic Ca2+ signaling in blood vessels","volume":"207","author":"Wier","year":"2017","journal-title":"Auton. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.tcb.2018.02.009","article-title":"Endoplasmic Reticulum-Mitochondrial Contactology: Structure and Signaling Functions","volume":"28","author":"Weaver","year":"2018","journal-title":"Trends Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"189","DOI":"10.7150\/ijbs.22896","article-title":"The Role of G Protein-coupled Receptor Kinases in Cancer","volume":"14","author":"Yu","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s12943-017-0747-z","article-title":"PKN2 in colon cancer cells inhibits M2 phenotype polarization of tumor-associated macrophages via regulating DUSP6-Erk1\/2 pathway","volume":"17","author":"Cheng","year":"2018","journal-title":"Mol. Cancer"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.ceb.2017.01.005","article-title":"AMPK signalling in health and disease","volume":"45","author":"Carling","year":"2017","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nrm.2017.95","article-title":"AMPK: Guardian of metabolism and mitochondrial homeostasis","volume":"19","author":"Herzig","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.neurobiolaging.2014.07.035","article-title":"Cross talk between PI3K-AKT-GSK-3beta and PP2A pathways determines tau hyperphosphorylation","volume":"36","author":"Wang","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1080\/15548627.2019.1586250","article-title":"TRAF6 inhibits colorectal cancer metastasis through regulating selective autophagic CTNNB1\/\u03b2-catenin degradation and is targeted for GSK3B\/GSK3\u03b2-mediated phosphorylation and degradation","volume":"15","author":"Wu","year":"2019","journal-title":"Autophagy"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1002\/jcb.20814","article-title":"Phosphorylation and glycosylation interplay: Protein modifications at hydroxy amino acids and prediction of signaling functions of the human \u03b23 integrin family","volume":"99","author":"Ahmad","year":"2006","journal-title":"J. Cell. Biochem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1002\/pmic.200300584","article-title":"Identification and characterization of phosphorylated proteins in the human pituitary","volume":"4","author":"Giorgianni","year":"2004","journal-title":"Proteomics"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s11102-006-8916-x","article-title":"Phosphoproteomic analysis of the human pituitary","volume":"9","author":"Zhao","year":"2006","journal-title":"Pituitary"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"835","DOI":"10.3389\/fendo.2019.00835","article-title":"Multiomics-Based Signaling Pathway Network Alterations in Human Non-functional Pituitary Adenomas","volume":"10","author":"Long","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.canlet.2018.08.002","article-title":"cAMP\/PKA-induced filamin A (FLNA) phosphorylation inhibits SST2 signal transduction in GH-secreting pituitary tumor cells","volume":"435","author":"Peverelli","year":"2018","journal-title":"Cancer Lett."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1038\/nrm.2017.86","article-title":"Mechanistic insights into precursor messenger RNA splicing by the spliceosome","volume":"18","author":"Shi","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1158\/2159-8290.CD-15-1020","article-title":"Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy","volume":"5","author":"Sotillo","year":"2015","journal-title":"Cancer Discov."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"V\u00e1zquez-Borrego, M.C., Fuentes-Fayos, A.C., Venegas-Moreno, E., Rivero-Cort\u00e9s, E., Dios, E., Moreno-Moreno, P., Madrazo-Atutxa, A., Rem\u00f3n, P., Solivera, J., and Wildemberg, L.E. (2019). Splicing machinery is dysregulated in pituitary neuroendocrine tumors and is associated with aggressiveness features. Cancers, 11.","DOI":"10.3390\/cancers11101439"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Mishra, A., Sipma, W., Veenhoff, L.M., Van der Giessen, E., and Onck, P.R. (2019). The Effect of FG-Nup Phosphorylation on NPC Selectivity: A One-Bead-Per-Amino-Acid Molecular Dynamics Study. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030596"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e201910070","DOI":"10.1083\/jcb.201910070","article-title":"Don\u2019t sugarcoat it: How glycocalyx composition influences cancer progression","volume":"219","author":"Buffone","year":"2020","journal-title":"J. Cell Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/joim.12465","article-title":"The glycocalyx and its significance in human medicine","volume":"280","author":"Tarbell","year":"2016","journal-title":"J. Intern. Med."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Kang, H., Wu, Q., Sun, A., Liu, X., Fan, Y., and Deng, X. (2018). Cancer Cell Glycocalyx and Its Significance in Cancer Progression. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092484"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1002\/bies.10165","article-title":"SNARE interactions in membrane trafficking: A perspective from mammalian central synapses","volume":"24","author":"Kavalali","year":"2002","journal-title":"Bioessays"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1046\/j.1471-4159.1999.0720614.x","article-title":"Differential phosphorylation of syntaxin and synaptosome-associated protein of 25 kDa (SNAP-25) isoforms","volume":"72","author":"Risinger","year":"1999","journal-title":"J. Neurochem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.tcb.2020.08.004","article-title":"Tight Junction Structure and Function Revisited","volume":"30","author":"Otani","year":"2020","journal-title":"Trends Cell Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.devcel.2018.10.017","article-title":"Pituicyte Cues Regulate the Development of Permeable Neuro-Vascular Interfaces","volume":"47","author":"Anbalagan","year":"2018","journal-title":"Dev. Cell"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Hashimoto, Y., Tachibana, K., Krug, S.M., Kunisawa, J., Fromm, M., and Kondoh, M. (2019). Potential for Tight Junction Protein-Directed Drug Development Using Claudin Binders and Angubindin-1. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20164016"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3783","DOI":"10.1016\/j.cub.2017.11.014","article-title":"Tension-Dependent Stretching Activates ZO-1 to Control the Junctional Localization of Its Interactors","volume":"27","author":"Spadaro","year":"2017","journal-title":"Curr. Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.1128\/MCB.00053-16","article-title":"Occludin S471 Phosphorylation Contributes to Epithelial Monolayer Maturation","volume":"36","author":"Bolinger","year":"2016","journal-title":"Mol. Cell. Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s12943-018-0804-2","article-title":"Kinase-targeted cancer therapies: Progress, challenges and future directions","volume":"17","author":"Bhullar","year":"2018","journal-title":"Mol. Cancer"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Yan, Y., Zhou, X.E., Xu, H.E., and Melcher, K. (2018). Structure and Physiological Regulation of AMPK. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113534"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10930-017-9696-z","article-title":"Phosphorylation: Implications in Cancer","volume":"36","author":"Singh","year":"2017","journal-title":"Protein J."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s12032-016-0758-4","article-title":"Multi-kinase inhibitors, AURKs and cancer","volume":"33","author":"Cicenas","year":"2016","journal-title":"Med. Oncol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature07668","article-title":"WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity","volume":"457","author":"Xiao","year":"2009","journal-title":"Nature"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1093\/nar\/gkv061","article-title":"Multiple facets of histone variant H2AX: A DNA double-strand-break marker with several biological functions","volume":"43","author":"Turinetto","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"35751","DOI":"10.1074\/jbc.M007476200","article-title":"Cell surface expression of calnexin, a molecular chaperone in the endoplasmic reticulum","volume":"275","author":"Okazaki","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1158\/2326-6066.CIR-18-0124","article-title":"Calnexin Impairs the Antitumor Immunity of CD4+ and CD8+ T Cells","volume":"7","author":"Chen","year":"2019","journal-title":"Cancer Immunol. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/s10014-017-0307-7","article-title":"New WHO classification of pituitary adenomas (4th edition): Assessment of pituitary transcription factors and the prognostic histological factors","volume":"35","author":"Nishioka","year":"2018","journal-title":"Brain Tumor Pathol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1007\/s12022-017-9498-z","article-title":"Overview of the 2017 WHO classification of pituitary tumors","volume":"28","author":"Mete","year":"2017","journal-title":"Endocr. Pathol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1385\/EP:14:1:49","article-title":"Hormone markers in pituitary adenomas: Changes within last decade resulting from improved method","volume":"14","author":"Saeger","year":"2003","journal-title":"Endocr. Pathol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1530\/eje.1.02326","article-title":"Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry","volume":"156","author":"Saeger","year":"2007","journal-title":"Eur. J. Endocrinol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"29282","DOI":"10.18632\/oncotarget.16502","article-title":"Plurihormonal cells of normal anterior pituitary: Facts and conclusions","volume":"8","author":"Mitrofanova","year":"2017","journal-title":"Oncotarget"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1373\/49.10.1740","article-title":"Heterogeneity analysis of the human pituitaryproteome","volume":"49","author":"Zhan","year":"2003","journal-title":"Clin. Chem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"10214","DOI":"10.1158\/0008-5472.CAN-05-0884","article-title":"Novel molecular signaling and classification of human clinically nonfunctional pituitary adenomas identified by gene expression profiling and proteomic analyses","volume":"65","author":"Moreno","year":"2005","journal-title":"Cancer Res."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Zhan, X., Wang, X., Long, Y., and Desiderio, D.M. (2014). Heterogeneity analysis of the proteomes in clinically nonfunctional pituitary adenomas. BMC Med. Genet., 7.","DOI":"10.1186\/s12920-014-0069-6"},{"key":"ref_94","first-page":"e170002","article-title":"Consideration of statistical vs. biological significances for omics data-based pathway network analysis","volume":"1","author":"Zhan","year":"2017","journal-title":"Med. One"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s11154-019-09509-9","article-title":"Vasopressin and Copeptin in health and disease","volume":"20","year":"2019","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/BFb0119577","article-title":"The mechanisms of aquaporin control in the renal collecting duct","volume":"141","author":"Klussmann","year":"2000","journal-title":"Rev. Physiol. Biochem. Pharmacol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/prd.12116","article-title":"The physiology of salivary secretion","volume":"70","author":"Proctor","year":"2016","journal-title":"Periodontol. 2000"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/9\/2225\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:54:05Z","timestamp":1760165645000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/9\/2225"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,27]]},"references-count":97,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["cells10092225"],"URL":"https:\/\/doi.org\/10.3390\/cells10092225","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,27]]}}}