{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T15:09:41Z","timestamp":1767971381059,"version":"3.49.0"},"reference-count":86,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T00:00:00Z","timestamp":1691107200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Israel Science Foundation","award":["180\/09"],"award-info":[{"award-number":["180\/09"]}]},{"name":"Israel Science Foundation","award":["1724\/11"],"award-info":[{"award-number":["1724\/11"]}]},{"name":"Israel Science Foundation","award":["1772\/13"],"award-info":[{"award-number":["1772\/13"]}]},{"name":"Israel Science Foundation","award":["1463\/18"],"award-info":[{"award-number":["1463\/18"]}]},{"name":"Singapore National Research Foundation","award":["180\/09"],"award-info":[{"award-number":["180\/09"]}]},{"name":"Singapore National Research Foundation","award":["1724\/11"],"award-info":[{"award-number":["1724\/11"]}]},{"name":"Singapore National Research Foundation","award":["1772\/13"],"award-info":[{"award-number":["1772\/13"]}]},{"name":"Singapore National Research Foundation","award":["1463\/18"],"award-info":[{"award-number":["1463\/18"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The p38 members of the mitogen-activated protein kinases (MAPKs) family mediate various cellular responses to stress conditions, inflammatory signals, and differentiation factors. They are constitutively active in chronic inflammatory diseases and some cancers. The differences between their transient effects in response to signals and the chronic effect in diseases are not known. The family is composed of four isoforms, of which p38\u03b1 seems to be abnormally activated in diseases. p38\u03b1 and p38\u03b2 are almost identical in sequence, structure, and biochemical and pharmacological properties, and the specific unique effects of each of them, if any, have not yet been revealed. This study aimed to reveal the specific effects induced by p38\u03b1 and p38\u03b2, both when transiently activated in response to stress and when chronically active. This was achieved via large-scale proteomics and phosphoproteomics analyses using stable isotope labeling of two experimental systems: one, mouse embryonic fibroblasts (MEFs) deficient in each of these p38 kinases and harboring either an empty vector or vectors expressing p38\u03b1WT, p38\u03b2WT, or intrinsically active variants of these MAPKs; second, induction of transient stress by exposure of MEFs, p38\u03b1\u2212\/\u2212, and p38\u03b2\u2212\/\u2212 MEFs to anisomycin. Significant differences in the repertoire of the proteome and phosphoproteome between cells expressing active p38\u03b1 and p38\u03b2 suggest distinct roles for each kinase. Interestingly, in both cases, the constitutive activation induced adaptations of the cells to the chronic activity so that known substrates of p38 were downregulated. Within the dramatic effect of p38s on the proteome and phosphoproteome, some interesting affected phosphorylation sites were those found in cancer-associated p53 and Hspb1 (HSP27) proteins and in cytoskeleton-associated proteins. Among these, was the stronger direct phosphorylation by p38\u03b1 of p53-Ser309, which was validated on the Ser315 in human p53. In summary, this study sheds new light on the differences between chronic and transient p38\u03b1 and p38\u03b2 signaling and on the specific targets of these two kinases.<\/jats:p>","DOI":"10.3390\/ijms241512442","type":"journal-article","created":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T09:27:48Z","timestamp":1691141268000},"page":"12442","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Differential Modulation of the Phosphoproteome by the MAP Kinases Isoforms p38\u03b1 and p38\u03b2"],"prefix":"10.3390","volume":"24","author":[{"given":"Dganit","family":"Melamed Kadosh","sequence":"first","affiliation":[{"name":"Faculty of Biology, Technion\u2014Israel Institute of Technology, Haifa 3200003, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonah","family":"Beenstock","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6977-3285","authenticated-orcid":false,"given":"David","family":"Engelberg","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel"},{"name":"Singapore-HUJ Alliance for Research and Enterprise, Mechanisms of Liver Inflammatory Diseases Program, National University of Singapore, Singapore 138602, Singapore"},{"name":"Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0504-3950","authenticated-orcid":false,"given":"Arie","family":"Admon","sequence":"additional","affiliation":[{"name":"Faculty of Biology, Technion\u2014Israel Institute of Technology, Haifa 3200003, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1128\/MMBR.00031-10","article-title":"Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases","volume":"75","author":"Cargnello","year":"2011","journal-title":"Microbiol. 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