{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T22:45:43Z","timestamp":1769208343641,"version":"3.49.0"},"reference-count":82,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82170912"],"award-info":[{"award-number":["82170912"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82370910"],"award-info":[{"award-number":["82370910"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004826","name":"Beijing Natural Science Foundation","doi-asserted-by":"publisher","award":["7252059"],"award-info":[{"award-number":["7252059"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Proteomes"],"abstract":"<jats:p>Background: Cleft palate (CP) is a prevalent craniofacial malformation, with the TGF\u03b2 pathway playing a critical role. Recent evidence links autophagy to regulating mouse embryonic palatal mesenchyme (MEPM) cells, but its interaction with TGF\u03b2-activated phosphorylation cascades remains largely unknown. Here, we investigated the interplay between these pathways during palatogenesis. Methods: H&amp;E and IHC analyses revealed increased expression of Beclin 1 and LC3 during the critical period of palatal shelf elevation and fusion (E13.5\u2013E15.5). Bulk RNA sequencing (Bulk RNA-seq) further revealed enrichment of autophagy-related pathways and their interaction with TGF\u03b2 signaling. TMT-based phosphoproteomics was performed on TGF\u03b22-treated MEPM cells. Results: We identified 23,471 peptides and 3952 proteins, including 6339 phosphopeptides corresponding to 2195 phosphoproteins. Differential analysis found 477 phosphopeptides with increased abundance and 53 with decreased abundance, revealing the enrichment of seven serine (p-Ser) motifs (RxxS, SDxD, SDxE, SP, SxDE, SxEE, SxxxxD) and one threonine (p-Thr) motif (TP). Notably, kinase-substrate enrichment analysis identified CSNK2A as a previously unrecognized phosphorylation regulator, together with MAPKs and CDKs. Functional enrichment showed significant involvement of mTOR, MAPK, and autophagy\/mitophagy pathways. Conclusions: Our findings revealed that TGF\u03b22 reshapes the MEPM phosphoproteome through Smad-independent pathway, expanding the palate-specific phospho-signaling atlas beyond the canonical Smad cascade.<\/jats:p>","DOI":"10.3390\/proteomes14010005","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T18:35:56Z","timestamp":1769193356000},"page":"5","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated Phosphoproteomics Identifies TGF\u03b2-Dependent Phosphorylation Events Linking Kinase Signaling to Autophagy in Palatogenesis"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9726-8766","authenticated-orcid":false,"given":"Xia","family":"Peng","sequence":"first","affiliation":[{"name":"Laboratory of Orofacial Development, Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, Capital Medical University, No. 9 Fanjiacun Road, FengTai District, Beijing 100070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Chen","sequence":"additional","affiliation":[{"name":"Laboratory of Orofacial Development, Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, Capital Medical University, No. 9 Fanjiacun Road, FengTai District, Beijing 100070, China"},{"name":"Department of Stomatology, Beijing Anzhen Hospital, Capital Medical University, No. 2 Anzhen Road, Chaoyang District, Beijing 100029, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyu","family":"Zheng","sequence":"additional","affiliation":[{"name":"Laboratory of Orofacial Development, Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, Capital Medical University, No. 9 Fanjiacun Road, FengTai District, Beijing 100070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xige","family":"Zhao","sequence":"additional","affiliation":[{"name":"Laboratory of Orofacial Development, Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, Capital Medical University, No. 9 Fanjiacun Road, FengTai District, Beijing 100070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yijia","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Orofacial Development, Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, Capital Medical University, No. 9 Fanjiacun Road, FengTai District, Beijing 100070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaotong","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Orofacial Development, Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, Capital Medical University, No. 9 Fanjiacun Road, FengTai District, Beijing 100070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Du","sequence":"additional","affiliation":[{"name":"Laboratory of Orofacial Development, Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, Capital Medical University, No. 9 Fanjiacun Road, FengTai District, Beijing 100070, China"},{"name":"Department of Geriatric Dentistry, Beijing Stomatological Hospital, Capital Medical University, No. 9 Fanjiacun Road, FengTai District, Beijing 100070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.jormas.2021.05.008","article-title":"Global prevalence of cleft palate, cleft lip and cleft palate and lip: A comprehensive systematic review and meta-analysis","volume":"123","author":"Salari","year":"2022","journal-title":"J. Stomatol. Oral. Maxillofac. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1111\/odi.15207","article-title":"Spectrum of Craniofacial and Oral Malformations in China, a Multicenter Study","volume":"31","author":"Duan","year":"2025","journal-title":"Oral. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/bs.ctdb.2022.10.006","article-title":"Genexenvironment associations in orofacial clefting","volume":"152","author":"Marazita","year":"2023","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/nrg2933","article-title":"Cleft lip and palate: Understanding genetic and environmental influences","volume":"12","author":"Dixon","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"ref_5","first-page":"1025","article-title":"Environmental and Genetic Risk Factors of Nonsyndromic and Syndromic Cleft Lip and Palate\u2014A Literature Review","volume":"3","author":"Egbunah","year":"2022","journal-title":"Ann. Surg. Edu."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/s41368-025-00347-x","article-title":"Administration of Porphyromonas gingivalis in pregnant mice enhances glycolysis and histone lactylation\/ADAM17 leading to cleft palate in offspring","volume":"17","author":"Zhao","year":"2025","journal-title":"Int. J. Oral. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s10565-025-10000-2","article-title":"Glycolysis regulates palatal mesenchyme proliferation through Pten-Glut1 axis via Pten classical and non-classical pathways","volume":"41","author":"Wang","year":"2025","journal-title":"Cell Biol. Toxicol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"344","DOI":"10.5115\/acb.25.060","article-title":"The developmental bases of cleft lip and cleft palate: Cellular and molecular mechanisms","volume":"58","author":"Guarino","year":"2025","journal-title":"Anat. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1242\/dev.067082","article-title":"Palatogenesis: Morphogenetic and molecular mechanisms of secondary palate development","volume":"139","author":"Bush","year":"2012","journal-title":"Development"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1111\/odi.14174","article-title":"Revisiting the embryogenesis of lip and palate development","volume":"28","author":"Hammond","year":"2022","journal-title":"Oral. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1128\/EC.01.1.11-21.2002","article-title":"Autophagy in the eukaryotic cell","volume":"1","author":"Reggiori","year":"2002","journal-title":"Eukaryot. Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/s41392-023-01608-z","article-title":"Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease","volume":"8","author":"Panwar","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1186\/s12964-025-02317-6","article-title":"Progress on multifunctional transmembrane protein ATG9A","volume":"23","author":"Lin","year":"2025","journal-title":"Cell Commun. Signal"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ke, P.Y. (2024). Molecular Mechanism of Autophagosome-Lysosome Fusion in Mammalian Cells. Cells, 13.","DOI":"10.3390\/cells13060500"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1080\/15548627.2022.2083807","article-title":"The fate of autophagosomal membrane components","volume":"19","author":"Wu","year":"2023","journal-title":"Autophagy"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1111\/j.1600-0854.2010.01103.x","article-title":"The role of autophagy during development in higher eukaryotes","volume":"11","author":"Nazio","year":"2010","journal-title":"Traffic"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhou, P., Wang, J., Wang, J., and Liu, X. (2024). When autophagy meets placenta development and pregnancy complications. Front. Cell Dev. Biol., 12.","DOI":"10.3389\/fcell.2024.1327167"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1007\/s11626-022-00704-8","article-title":"Chloroquine regulates the proliferation and apoptosis of palate development on mice embryo by activating P53 through blocking autophagy in vitro","volume":"58","author":"Chen","year":"2022","journal-title":"In Vitro Cell Dev. Biol. Anim."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"81909","DOI":"10.1007\/s11356-022-21496-0","article-title":"Autophagy triggered by the ROS\/ERK signaling pathway protects mouse embryonic palatal cells from apoptosis induced by nicotine","volume":"29","author":"Chen","year":"2022","journal-title":"Env. Sci. Pollut. Res. Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1002\/1096-8652(200101)66:1<12::AID-AJH1001>3.0.CO;2-I","article-title":"Role of transforming growth factor \u03b21 in microvascular endothelial cell apoptosis associated with thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome","volume":"66","author":"Mauro","year":"2001","journal-title":"Am. J. Hematol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"128","DOI":"10.21037\/atm.2019.02.22","article-title":"AMBRA1-mediated autophagy and apoptosis associated with an epithelial-mesenchymal transition in the development of cleft palate induced by all-trans retinoic acid","volume":"7","author":"Shu","year":"2019","journal-title":"Ann. Transl. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5353","DOI":"10.1093\/emboj\/16.17.5353","article-title":"TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4","volume":"16","author":"Nakao","year":"1997","journal-title":"EMBO J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"119284","DOI":"10.1016\/j.bbamcr.2022.119284","article-title":"Autophagy regulates transforming growth factor \u03b2 signaling and receptor trafficking","volume":"1869","author":"Trelford","year":"2022","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Cell Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/emboj.2009.8","article-title":"TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells","volume":"28","author":"Fumarola","year":"2009","journal-title":"EMBO J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/S0163-7258(98)00056-4","article-title":"Protein phosphorylation and signal transduction","volume":"82","author":"Graves","year":"1999","journal-title":"Pharmacol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/cr.2008.327","article-title":"Phospho-control of TGF-\u03b2 superfamily signaling","volume":"19","author":"Wrighton","year":"2009","journal-title":"Cell Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"101783","DOI":"10.1016\/j.tice.2022.101783","article-title":"Comparative analysis of mouse embryonic palatal mesenchymal cells isolated by two primary culture methods","volume":"76","author":"Wang","year":"2022","journal-title":"Tissue Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1080\/10520295.2018.1552018","article-title":"ALK5 is essential for tooth germ differentiation during tooth development","volume":"94","author":"Guo","year":"2019","journal-title":"Biotech. Histochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1007\/s00726-011-1111-z","article-title":"Enrichment techniques employed in phosphoproteomics","volume":"43","author":"Honys","year":"2012","journal-title":"Amino Acids"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.diff.2023.05.002","article-title":"Osteogenic microenvironment affects palatal development through glycolysis","volume":"133","author":"Peng","year":"2023","journal-title":"Differentiation"},{"key":"ref_33","first-page":"333","article-title":"LC3 and Beclin-1 as markers of autophagic activity in breast cancer","volume":"43","author":"Nurdinov","year":"2021","journal-title":"J. Clin. Pract. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1172\/JCI61498","article-title":"Modulation of noncanonical TGF-\u03b2 signaling prevents cleft palate in Tgfbr2 mutant mice","volume":"122","author":"Iwata","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4765","DOI":"10.1091\/mbc.e05-03-0257","article-title":"Phosphoproteome profiling of transforming growth factor (TGF)-\u03b2 signaling: Abrogation of TGF\u03b21-dependent phosphorylation of transcription factor-II-I (TFII-I) enhances cooperation of TFII-I and Smad3 in transcription","volume":"16","author":"Stasyk","year":"2005","journal-title":"Mol. Biol. Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nature02006","article-title":"Smad-dependent and Smad-independent pathways in TGF-\u03b2 family signalling","volume":"425","author":"Derynck","year":"2003","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1146\/annurev.pharmtox.011008.145606","article-title":"Global and site-specific quantitative phosphoproteomics: Principles and applications","volume":"49","author":"Macek","year":"2009","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1002\/wics.101","article-title":"Principal component analysis","volume":"2","author":"Abdi","year":"2010","journal-title":"Wiley Interdiscip. Rev. Comput. Stat."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Chen, L., Zhang, Y.-H., Wang, S., Zhang, Y., Huang, T., and Cai, Y.-D. (2017). Prediction and analysis of essential genes using the enrichments of gene ontology and KEGG pathways. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0184129"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"D353","DOI":"10.1093\/nar\/gkw1092","article-title":"KEGG: New perspectives on genomes, pathways, diseases and drugs","volume":"45","author":"Kanehisa","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e1655","DOI":"10.1002\/mgg3.1655","article-title":"Co-occurrence of orofacial clefts and clubfoot phenotypes in a sub-Saharan African cohort: Whole-exome sequencing implicates multiple syndromes and genes","volume":"9","author":"Gowans","year":"2021","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.3892\/mmr.2016.4802","article-title":"Gene expression profiling analysis contributes to understanding the association between non-syndromic cleft lip and palate, and cancer","volume":"13","author":"Wang","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2774","DOI":"10.1093\/bioinformatics\/bty1058","article-title":"MoMo: Discovery of statistically significant post-translational modification motifs","volume":"35","author":"Cheng","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3489","DOI":"10.1093\/bioinformatics\/btx415","article-title":"The KSEA App: A web-based tool for kinase activity inference from quantitative phosphoproteomics","volume":"33","author":"Wiredja","year":"2017","journal-title":"Bioinformatics"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"112807","DOI":"10.1016\/j.celrep.2023.112807","article-title":"Activation of autophagy depends on Atg1\/Ulk1-mediated phosphorylation and inhibition of the Hsp90 chaperone machinery","volume":"42","author":"Backe","year":"2023","journal-title":"Cell Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1186\/s13287-019-1340-8","article-title":"Mouse embryonic palatal mesenchymal cells maintain stemness through the PTEN-Akt-mTOR autophagic pathway","volume":"10","author":"Shi","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.bbrc.2017.04.130","article-title":"Autophagy regulates Endothelial-Mesenchymal transition by decreasing the phosphorylation level of Smad3","volume":"487","author":"Wang","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1002\/ddr.21868","article-title":"Naringenin inhibits autophagy and epithelial-mesenchymal transition of human lens epithelial cells by regulating the Smad2\/3 pathway","volume":"83","author":"Li","year":"2022","journal-title":"Drug Dev. Res."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Zhang, D., Zhu, H., Yu, X., Wang, L., Wen, Y., Zhang, L., Tong, J., and Shen, Y. (2022). Blue light attenuates TGF-\u03b22-induced epithelial-mesenchymal transition in human lens epithelial cells via autophagy impairment. BMC Ophthalmol., 22.","DOI":"10.1186\/s12886-022-02691-6"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1242\/dev.103.Supplement.41","article-title":"Palate development","volume":"103","author":"Ferguson","year":"1988","journal-title":"Development"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/0003-9969(92)90024-3","article-title":"The effects of epidermal growth factor, transforming growth factors alpha and beta and platelet-derived growth factor on murine palatal shelves in organ culture","volume":"37","author":"Dixon","year":"1992","journal-title":"Arch. Oral. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Murillo Arroyo, F.J., Maldonado Bautista, E., Barrio, M., R\u00edo Sevilla, A.D., L\u00f3pez, Y., Mart\u00ednez Sanz, E., Gonz\u00e1lez, I., Mart\u00edn \u00c1lvaro, M.C., Casado G\u00f3mez, I., and Mart\u00ednez \u00c1lvarez, M.C. (2009). Interactions Between TGF-beta1 and TGF-beta3 and Their Role in Medial Edge Epithelium Cell Death and Palatal Fusion In Vitro, Elsevier.","DOI":"10.1016\/j.diff.2008.10.004"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.ydbio.2007.09.034","article-title":"Tgfb1 expressed in the Tgfb3 locus partially rescues the cleft palate phenotype of Tgfb3 null mutants","volume":"312","author":"Yang","year":"2007","journal-title":"Dev. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3869","DOI":"10.1242\/dev.126.17.3869","article-title":"Pathogenesis of cleft palate in TGF-\u03b23 knockout mice","volume":"126","author":"Taya","year":"1999","journal-title":"Development"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1242\/dev.109.3.585","article-title":"Differential expression of TGF beta isoforms in murine palatogenesis","volume":"109","author":"Fitzpatrick","year":"1990","journal-title":"Development"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/0012-1606(90)90401-4","article-title":"Differential expression of genes encoding TGFs \u03b21, \u03b22, and \u03b23 during murine palate formation","volume":"141","author":"Pelton","year":"1990","journal-title":"Dev. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/238282a0","article-title":"Role for protein phosphorylation in meiosis and in the early cleavage phase of amphibian embryonic development","volume":"238","author":"Morrill","year":"1972","journal-title":"Nature"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/nature08102","article-title":"Unlimited multistability in multisite phosphorylation systems","volume":"460","author":"Thomson","year":"2009","journal-title":"Nature"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1177\/0022034515583532","article-title":"Gpr177-mediated Wnt signaling is required for secondary palate development","volume":"94","author":"Liu","year":"2015","journal-title":"J. Dent. Res."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Morioka, Y., Nam, J.-M., and Ohashi, T. (2017). Nik-related kinase regulates trophoblast proliferation and placental development by modulating AKT phosphorylation. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0171503"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Li, S., Li, S., Han, Y., Tong, C., Wang, B., Chen, Y., and Jiang, J. (2016). Regulation of smoothened phosphorylation and high-level hedgehog signaling activity by a plasma membrane associated kinase. PLoS Biol., 14.","DOI":"10.1371\/journal.pbio.1002481"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0925-4773(99)00089-1","article-title":"Protein-tyrosine phosphatases in development","volume":"85","year":"1999","journal-title":"Mech. Dev."},{"key":"ref_64","first-page":"737740","article-title":"Smads: Transcriptional activators of TGF-beta responses","volume":"95","author":"XH","year":"1998","journal-title":"Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.cell.2008.12.028","article-title":"The secret life of Smad4","volume":"136","author":"Wrana","year":"2009","journal-title":"Cell"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1016\/j.cell.2006.05.015","article-title":"A phosphatase controls the fate of receptor-regulated Smads","volume":"125","author":"Schilling","year":"2006","journal-title":"Cell"},{"key":"ref_67","first-page":"559","article-title":"Negative feedback of glycolysis and oxidative phosphorylation: Mechanisms of and reasons for it","volume":"80","author":"Sokolov","year":"2015","journal-title":"Biochemistry"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"5764","DOI":"10.1038\/sj.onc.1208927","article-title":"TGF-\u03b2 and epithelial-to-mesenchymal transitions","volume":"24","author":"Zavadil","year":"2005","journal-title":"Oncogene"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Suttorp, C.M., van Rheden, R.E., van Dijk, N.W., Helmich, M.P., Kuijpers-Jagtman, A.M., and Wagener, F.A. (2020). Heme oxygenase protects against placental vascular inflammation and abortion by the alarmin heme in mice. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21155385"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1074\/mcp.RA119.001504","article-title":"Phosphotyrosine-based Phosphoproteomics for Target Identification and Drug Response Prediction in AML Cell Lines","volume":"19","author":"Cloos","year":"2020","journal-title":"Mol. Cell Proteom."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1158\/0008-5472.CAN-20-3804","article-title":"High-Density, Targeted Monitoring of Tyrosine Phosphorylation Reveals Activated Signaling Networks in Human Tumors","volume":"81","author":"Stopfer","year":"2021","journal-title":"Cancer Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"108731","DOI":"10.1016\/j.reprotox.2024.108731","article-title":"AKT\/mTOR-mediated autophagic signaling is associated with TCDD-induced cleft palate","volume":"130","author":"Zhang","year":"2024","journal-title":"Reprod. Toxicol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1186\/s10020-024-00960-2","article-title":"Lhx6 deficiency causes human embryonic palatal mesenchymal cell mitophagy dysfunction in cleft palate","volume":"30","author":"Luo","year":"2024","journal-title":"Mol. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1080\/15548627.2015.1060386","article-title":"ATG16L1 phosphorylation is oppositely regulated by CSNK2\/casein kinase 2 and PPP1\/protein phosphatase 1 which determines the fate of cardiomyocytes during hypoxia\/reoxygenation","volume":"11","author":"Song","year":"2015","journal-title":"Autophagy"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1053\/j.gastro.2020.06.088","article-title":"Activating Transcription Factor 6 Mediates Inflammatory Signals in Intestinal Epithelial Cells Upon Endoplasmic Reticulum Stress","volume":"159","author":"Stengel","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Sorriento, D., Rusciano, M.R., Visco, V., Fiordelisi, A., Cerasuolo, F.A., Poggio, P., Ciccarelli, M., and Iaccarino, G. (2021). The metabolic role of GRK2 in insulin resistance and associated conditions. Cells, 10.","DOI":"10.3390\/cells10010167"},{"key":"ref_77","first-page":"13","article-title":"Genetic variation in RPS6KA1, RPS6KA2, RPS6KB1, RPS6KB2, and PDK1 and risk of colon or rectal cancer","volume":"706","author":"Slattery","year":"2011","journal-title":"Mutat. Res. Fundam. Mol. Mech. Mutagen."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1590\/S0100-879X2005000300003","article-title":"NFAT transcription factors: From cell cycle to tumor development","volume":"38","author":"Viola","year":"2005","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.tibs.2011.03.001","article-title":"Modulating stress responses by the UPRosome: A matter of life and death","volume":"36","author":"Woehlbier","year":"2011","journal-title":"Trends Biochem. Sci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"7683","DOI":"10.1093\/nar\/gkt563","article-title":"The eIF2\u03b1\/ATF4 pathway is essential for stress-induced autophagy gene expression","volume":"41","author":"Maurin","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1038\/s41467-019-09418-0","article-title":"FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism","volume":"10","author":"Sakaguchi","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3444","DOI":"10.1074\/mcp.O113.034181","article-title":"Status of large-scale analysis of post-translational modifications by mass spectrometry","volume":"12","author":"Olsen","year":"2013","journal-title":"Mol. Cell Proteom."}],"container-title":["Proteomes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-7382\/14\/1\/5\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T18:55:06Z","timestamp":1769194506000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-7382\/14\/1\/5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,23]]},"references-count":82,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["proteomes14010005"],"URL":"https:\/\/doi.org\/10.3390\/proteomes14010005","relation":{},"ISSN":["2227-7382"],"issn-type":[{"value":"2227-7382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,23]]}}}