CCM2 mediates death signaling by the TrkA receptor tyrosine kinase.
The TrkA receptor tyrosine kinase is crucial for differentiation and survival of nerve-growth-factor-dependent neurons. Paradoxically, TrkA also induces cell death in pediatric tumor cells of neural origin, via an unknown mechanism. Here, we show that CCM2, a gene product associated with cerebral cavernous malformations, interacts with the juxtamembrane region of TrkA via its phosphotyrosine binding (PTB) domain and mediates TrkA-induced death in diverse cell types. Both the PTB and Karet domains of CCM2 are required for TrkA-dependent cell death, such that the PTB domain determines the specificity of the interaction, and the Karet domain links to death pathways. Downregulation of CCM2 in medulloblastoma or neuroblastoma cells attenuates TrkA-dependent death. Combined high expression levels of CCM2 and TrkA are correlated with long-term survival in a large cohort of human neuroblastoma patients. Thus, CCM2 is a key mediator of TrkA-dependent cell death in pediatric neuroblastic tumors.
Harel
Liraz
L
Department of Biological Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel.
Costa
Barbara
B
Tcherpakov
Marianna
M
Zapatka
Marc
M
Oberthuer
Andre
A
Hansford
Loen M
LM
Vojvodic
Milijana
M
Levy
Zehava
Z
Chen
Zhe-Yu
ZY
Lee
Francis S
FS
Avigad
Smadar
S
Yaniv
Isaac
I
Shi
Leming
L
Eils
Roland
R
Fischer
Matthias
M
Brors
Benedikt
B
Kaplan
David R
DR
Fainzilber
Mike
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D008527:Medulloblastoma / Q000503:physiopathology; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009447:Neuroblastoma / Q000175:diagnosis / Q000503:physiopathology*; D016716:PC12 Cells; D011379:Prognosis; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism
C502544:CCM2 protein, human; D002352:Carrier Proteins; D008840:Microfilament Proteins; D020800:Receptor, Nerve Growth Factor; C480498:osmosensing scaffold for MEKK3 protein, mouse; D020917:Receptor, trkA; D020813:Receptor, trkB