title: CCM2 mediates death signaling by the TrkA receptor tyrosine kinase.
abstract: 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.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Liraz
authors.initials: L
authors.lastname: Harel
authors.forename: Barbara
authors.initials: B
authors.lastname: Costa
authors.forename: Marianna
authors.initials: M
authors.lastname: Tcherpakov
authors.forename: Marc
authors.initials: M
authors.lastname: Zapatka
authors.forename: Andre
authors.initials: A
authors.lastname: Oberthuer
authors.forename: Loen M
authors.initials: LM
authors.lastname: Hansford
authors.forename: Milijana
authors.initials: M
authors.lastname: Vojvodic
authors.forename: Zehava
authors.initials: Z
authors.lastname: Levy
authors.forename: Zhe-Yu
authors.initials: ZY
authors.lastname: Chen
authors.forename: Francis S
authors.initials: FS
authors.lastname: Lee
authors.forename: Smadar
authors.initials: S
authors.lastname: Avigad
authors.forename: Isaac
authors.initials: I
authors.lastname: Yaniv
authors.forename: Leming
authors.initials: L
authors.lastname: Shi
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
authors.forename: Mike
authors.initials: M
authors.lastname: Fainzilber
mesh_terms: 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
chemical_list: 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