Kinase suppressor of Ras is ceramide-activated protein kinase.
A proline-directed serine/threonine ceramide-activated protein (CAP) kinase mediates transmembrane signaling through the sphingomyelin pathway. CAP kinase reportedly initiates proinflammatory TNF alpha action by phosphorylating and activating Raf-1. The present studies delineate kinase suppressor of Ras (KSR), identified genetically in Caenorhabditis elegans and Drosophila, as CAP kinase. Mouse KSR, like CAP kinase, renatures and autophosphorylates as a 100-kDa membrane-bound polypeptide. KSR overexpression constitutively activates Raf-1. TNF alpha or ceramide analogs markedly enhance KSR autophosphorylation and its ability to complex with, phosphorylate, and activate Raf-1. In vitro, low nanomolar concentrations of natural ceramide stimulate KSR to autophosphorylate, and transactivate Raf-1. Other lipid second messengers were ineffective. Moreover, Thr269 the Raf-1 site phosphorylated by CAP kinase, is also recognized by KSR. Thus, by previously established criteria, KSR appears to be CAP kinase.
Zhang
Y
Y
Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Yao
B
B
Delikat
S
S
Bayoumy
S
S
Lin
X H
XH
Basu
S
S
McGinley
M
M
Chan-Hui
P Y
PY
Lichenstein
H
H
Kolesnick
R
R
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells / Q000201:enzymology; D017173:Caenorhabditis elegans; D002518:Ceramides / Q000494:pharmacology; D004330:Drosophila; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000502:physiology; D010766:Phosphorylation; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000494:pharmacology*; D019908:Proto-Oncogene Proteins c-raf; D015398:Signal Transduction / Q000502:physiology*; D013912:Threonine / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D018631:ras Proteins / Q000037:antagonists & inhibitors*
D002518:Ceramides; D014409:Tumor Necrosis Factor-alpha; D013912:Threonine; D011494:Protein Kinases; C097199:KSR-1 protein kinase; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins