{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T21:24:36Z","timestamp":1790889876887,"version":"4.1.0"},"reference-count":0,"publisher":"National Academy of Sciences","issue":"22","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1991,11,15]]},"abstract":"<jats:p>Recent investigations have identified a signal-transduction system involving sphingomyelin and derivatives. In this paradigm, sphingomyelin hydrolysis by a sphingomyelinase generates ceramide, which may be converted to the protein kinase C inhibitor sphingosine or to ceramide 1-phosphate. Ceramide may have second-messenger function because it induces epidermal growth factor receptor phosphorylation, presumably on Thr-669 in A-431 cells. The present studies describe a kinase that may mediate ceramide action. With a 19-amino acid epidermal growth factor receptor peptide containing Thr-669, a membrane-bound activity that phosphorylated the peptide was detected in A-431 cells. Activity was linearly related to ATP (0.3-300 microM) and peptide concentration (0.02-1 mg\/ml), possessed a physiologic pH optimum (pH 7.0-7.4), and was Mg(2+)-dependent. Other cations--Ca2+, Mn2+, and Zn(2+)--were ineffective. Natural and synthetic ceramide induced time- and concentration-dependent enhancement of kinase activity. Ceramide (0.5 microM) increased kinase activity 2-fold by 30 s, and activity remained elevated for at least 15 min. As little as 0.001 microM ceramide was effective, and 1 microM ceramide induced maximal phosphorylation. Sphingosine was similarly effective. Because tumor necrosis factor (TNF) alpha rapidly induces sphingomyelin hydrolysis to ceramide during monocytic differentiation of HL-60 cells, its effects on kinase activity were assessed. Kinase activity was increased 1.5-fold at 5 min and 2-fold at 2 hr in membranes derived from TNF-stimulated cells. The effective concentration range was 3 pM-30 nM TNF. Exogenous ceramide induced a similar effect. In sum, these studies demonstrate the existence of an unusual Mg(2+)-dependent ceramide-activated protein kinase that may mediate some aspects of TNF-alpha function.<\/jats:p>","DOI":"10.1073\/pnas.88.22.10009","type":"journal-article","created":{"date-parts":[[2006,5,31]],"date-time":"2006-05-31T07:50:38Z","timestamp":1149061838000},"page":"10009-10013","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":275,"title":["Characterization of a ceramide-activated protein kinase: stimulation by tumor necrosis factor alpha."],"prefix":"10.1073","volume":"88","author":[{"given":"S","family":"Mathias","sequence":"first","affiliation":[{"name":"Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, NY 10021."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K A","family":"Dressler","sequence":"additional","affiliation":[{"name":"Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, NY 10021."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R N","family":"Kolesnick","sequence":"additional","affiliation":[{"name":"Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, NY 10021."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1991,11,15]]},"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.88.22.10009","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T13:20:00Z","timestamp":1649856000000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.88.22.10009"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1991,11,15]]},"references-count":0,"journal-issue":{"issue":"22","published-print":{"date-parts":[[1991,11,15]]}},"alternative-id":["10.1073\/pnas.88.22.10009"],"URL":"https:\/\/doi.org\/10.1073\/pnas.88.22.10009","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[1991,11,15]]},"assertion":[{"value":"1991-11-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}