{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T08:52:08Z","timestamp":1773391928414,"version":"3.50.1"},"reference-count":124,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioinform."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>TNIK (Traf2- and Nck-interacting kinase) is a serine\/threonine kinase that plays a crucial role in cytoskeletal organization, Wnt pathway activation, and cancer progression. Recent studies have implicated the role of TNIK in oncogenic signaling pathways and neuropsychiatric regulation. However, the phosphosignaling dynamics of TNIK remain largely unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To explore TNIK phosphoregulation, we systematically assembled and integrated global human phosphoproteomic datasets. We identified the predominant phosphosites based on the frequency. Relative solvent accessibility (RSA) and Phosphosite accessibility index (PAI) were calculated to determine the solvent exposure and structural flexibility of TNIK predominant phosphosites. To assess the functional significance of TNIK, we examined proteins that were differentially co-regulated with its predominant phosphosite, along with the corresponding upstream kinases, downstream substrates, and interacting proteins.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Analysis of the global human cellular phosphoproteome datasets revealed phosphosites S640, S680, S707, and S769 of TNIK to be the most frequently perturbed phosphosites across diverse experimental conditions. The results of the RSA and PAI analysis revealed that the predominant sites are located within highly solvent-exposed and structurally flexible regions. Notably, we obtained a large number of co-regulated proteins that were associated with cell growth, carcinogenesis, and apoptosis. The interactors identified were primarily enriched towards carcinogenesis. Our analysis revealed PRKAA1 and RPS6KB2 as robust upstream kinases of TNIK_S640 and TNIK_S707. We also identified many proteins involved in RNA splicing, cytoskeletal organisation, and cell migration as potential downstream substrates of TNIK.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Considering the challenges in targeted experimental analysis of these sites, a global co-regulation analysis approach was employed. Our results show that these phosphorylation sites in TNIK can influence carcinogenesis and related biological functions. It offers new insights into TNIK-mediated cellular functions, deepening our comprehension of its involvement in carcinogenesis and RNA splicing.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fbinf.2026.1722876","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T06:46:51Z","timestamp":1773384411000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A system-wide investigation into the phosphoregulatory network of TNIK and its cellular implications"],"prefix":"10.3389","volume":"6","author":[{"given":"Akhila","family":"Sheela","sequence":"first","affiliation":[{"name":"Centre for Integrative Omics Data Science (CIODS), Yenepoya (Deemed to be University)","place":["Mangalore, Karnataka, India"]}]},{"given":"Suhail","family":"Subair","sequence":"additional","affiliation":[{"name":"Centre for Integrative Omics Data Science (CIODS), Yenepoya (Deemed to be University)","place":["Mangalore, Karnataka, India"]}]},{"given":"Samseera","family":"Ummar","sequence":"additional","affiliation":[{"name":"Centre for Integrative Omics Data Science (CIODS), Yenepoya (Deemed to be University)","place":["Mangalore, Karnataka, India"]}]},{"given":"Althaf","family":"Mahin","sequence":"additional","affiliation":[{"name":"Centre for Integrative Omics Data Science (CIODS), Yenepoya (Deemed to be University)","place":["Mangalore, Karnataka, India"]}]},{"given":"Athira Perunelly","family":"Gopalakrishnan","sequence":"additional","affiliation":[{"name":"Centre for Integrative Omics Data Science (CIODS), Yenepoya (Deemed to be University)","place":["Mangalore, Karnataka, India"]}]},{"given":"Rajesh","family":"Raju","sequence":"additional","affiliation":[{"name":"Centre for Integrative Omics Data Science (CIODS), Yenepoya (Deemed to be University)","place":["Mangalore, Karnataka, India"]}]},{"given":"Sowmya","family":"Soman","sequence":"additional","affiliation":[{"name":"Centre for Integrative Omics Data Science (CIODS), Yenepoya (Deemed to be University)","place":["Mangalore, Karnataka, India"]}]}],"member":"1965","published-online":{"date-parts":[[2026,3,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1042\/0264-6021:3540149","article-title":"LIM-kinase 2 induces formation of stress fibres, focal adhesions and membrane blebs, dependent on its activation by rho-associated kinase-catalysed phosphorylation at threonine-505","volume":"354","author":"Amano","year":"2001","journal-title":"Biochem. 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