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In this study, we analyzed 3825 global human cellular phosphoproteome studies, identifying 430 qualitative profiles and 55 quantitative differential datasets featuring high-confidence Class-1 phosphosites (localization probability \u2265 75%; A-score \u2265 13). Notably, S136 and S138 emerged as predominant phosphorylation sites outside the kinase domain. These sites showed frequent detection and differential expression in liver, lung, and head and neck cancers, as documented in PhosphositePlus. We identified a high-confidence set of co-regulated phosphoproteins, including SQSTM1, SRRT, RPS6, TP53BP1, TNKS1BP1, THUMPD1, OTUD4, and TCEA1. These proteins link CLK4 to critical pathways, including RNA splicing, autophagy, DNA damage response, and cancer progression. Binary interactors, including SRRM2, Interacts with SPT6 1 (IWS1), RBBP6, ZC3H18, BUD13, and DYRK1A, further connect CLK4 to RNA processing and splicing. Predicted downstream substrates, such as CCNL2, CDK11B, PRDX6, YTHDC1, RBM15, SRRM1, SFSWAP, HNRNPU, and DOCK7, highlight CLK4\u2019s broad regulatory scope. Upstream kinases were also predicted for S136 and S138. Site-resolved analyses revealed tumor-specific dysregulation of CLK4 phosphorylation at key residues. Co-occurring phosphosite alterations and nearby somatic mutations suggest disrupted CLK4 regulation in cancer. Overall, this study provides a comprehensive phosphoproteomic resource that maps CLK4\u2019s co-regulatory networks, paving the way for mechanistic investigations and targeted cancer therapies.<\/jats:p>","DOI":"10.1177\/15578100261470540","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T11:44:41Z","timestamp":1784720681000},"page":"594-608","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Global Phosphoproteome Analysis Identifies CLK4 Co-Regulatory Pathways Driving Tumor-Specific Dysregulation"],"prefix":"10.1177","volume":"30","author":[{"given":"Apoorva","family":"Pai","sequence":"first","affiliation":[{"name":"Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, Karnataka, India."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leona","family":"Dcunha","sequence":"additional","affiliation":[{"name":"Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, Karnataka, India."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athira Perunelly","family":"Gopalakrishnan","sequence":"additional","affiliation":[{"name":"Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, Karnataka, India."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samseera","family":"Ummar","sequence":"additional","affiliation":[{"name":"Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, Karnataka, India."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athira C.","family":"Rajeev","sequence":"additional","affiliation":[{"name":"Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, Karnataka, India."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2319-121X","authenticated-orcid":false,"given":"Rajesh","family":"Raju","sequence":"additional","affiliation":[{"name":"Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, Karnataka, India."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"e_1_3_4_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg056"},{"key":"e_1_3_4_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241411684"},{"key":"e_1_3_4_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2020.115962"},{"key":"e_1_3_4_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-0669-3"},{"key":"e_1_3_4_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2008.12.023"},{"key":"e_1_3_4_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1375942"},{"key":"e_1_3_4_8_1","doi-asserted-by":"publisher","DOI":"10.7150\/jca.24896"},{"key":"e_1_3_4_9_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20222056"},{"key":"e_1_3_4_10_1","volume-title":"Probe Reports from the NIH Molecular Libraries Program","author":"Coombs TC","year":"2012","unstructured":"Coombs TC, , Tanega C, , Shen M, et al. \u2018Identification of selective inhibitors of cdc2-like kinases 1 and 4 (Clk1, Clk4)\u2019. 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