STK25 protein mediates TrkA and CCM2 protein-dependent death in pediatric tumor cells of neural origin.
The TrkA receptor tyrosine kinase induces death in medulloblastoma cells via an interaction with the cerebral cavernous malformation 2 (CCM2) protein. We used affinity proteomics to identify the germinal center kinase class III (GCKIII) kinases STK24 and STK25 as novel CCM2 interactors. Down-modulation of STK25, but not STK24, rescued medulloblastoma cells from NGF-induced TrkA-dependent cell death, suggesting that STK25 is part of the death-signaling pathway initiated by TrkA and CCM2. CCM2 can be phosphorylated by STK25, and the kinase activity of STK25 is required for death signaling. Finally, STK25 expression in tumors is correlated with positive prognosis in neuroblastoma patients. These findings delineate a death-signaling pathway downstream of neurotrophic receptor tyrosine kinases that may provide targets for therapeutic intervention in pediatric tumors of neural origin.
Department of Biological Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel. barbara.costa@weizmann.ac.il
Barbara
B
Costa
Michelle J
MJ
Kean
Volker
V
Ast
James D R
JD
Knight
Alice
A
Mett
Zehava
Z
Levy
Derek F
DF
Ceccarelli
Beatriz Gonzalez
BG
Badillo
Roland
R
Eils
Rainer
R
König
Anne-Claude
AC
Gingras
Mike
M
Fainzilber
D000293:Adolescent; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000099317:Hippo Kinases
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D020917:Receptor, trkA; C502544:CCM2 protein, human; C480498:osmosensing scaffold for MEKK3 protein, mouse; C530661:Stk25 protein, mouse; D000099317:Hippo Kinases; C530660:STK25 protein, human