TY - JOUR
T1 - STK25 protein mediates TrkA and CCM2 protein-dependent death in pediatric tumor cells of neural origin
AU - Costa, Barbara
AU - Kean, Michelle J.
AU - Ast, Volker
AU - Knight, James D. R.
AU - Mett, Alice
AU - Levy, Zehava
AU - Ceccarelli, Derek F.
AU - Badillo, Beatriz Gonzalez
AU - Eils, Roland
AU - Koenig, Rainer
AU - Gingras, Anne-Claude
AU - Fainzilber, Mike
N1 - European Union (Endocyte Network); German-Israeli Cooperation in Cancer Research [CA 140]; Canadian Institutes of Health Research, Nationales Genom-Forschungs-Netz (NGFN+) project ENGINE [01GS0898]; Bundesministerium fur Bildung, Wissenschaft, Forschung und Technologie CancerSys-Verbundprojekt: MYCNET [0316076C]; Lombroso postdoctoral fellowship; Banting and Best Canada Graduate ScholarshipThis work was supported by the European Union (Endocyte Network), the German-Israeli Cooperation in Cancer Research (CA 140), the Canadian Institutes of Health Research, Nationales Genom-Forschungs-Netz (NGFN+) project ENGINE (01GS0898), and the Bundesministerium fur Bildung, Wissenschaft, Forschung und Technologie CancerSys-Verbundprojekt: MYCNET (0316076C), a Lombroso postdoctoral fellowship (to B. C.), and a Banting and Best Canada Graduate Scholarship (to M. J. K.).
PY - 2012/8/24
Y1 - 2012/8/24
N2 - The TrkA receptor tyrosine kinase induces death in medullo-blastoma cells via an interaction with the cerebral cavernous malformation 2 (CCM2) protein.Weused 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.
AB - The TrkA receptor tyrosine kinase induces death in medullo-blastoma cells via an interaction with the cerebral cavernous malformation 2 (CCM2) protein.Weused 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.
UR - http://www.scopus.com/inward/record.url?scp=84865519133&partnerID=8YFLogxK
U2 - 10.1074/jbc.C112.345397
DO - 10.1074/jbc.C112.345397
M3 - مقالة
SN - 0021-9258
VL - 287
SP - 29285
EP - 29289
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 35
ER -