%0 Journal Article %1 harel2009mediates %A Harel, Liraz %A Costa, Barbara %A Tcherpakov, Marianna %A Zapatka, Marc %A Oberthuer, Andre %A Hansford, Loen M. %A Vojvodic, Milijana %A Levy, Zehava %A Chen, Zhe-Yu %A Lee, Francis S. %A Avigad, Smadar %A Yaniv, Isaac %A Shi, Leming %A Eils, Roland %A Fischer, Matthias %A Brors, Benedikt %A Kaplan, David R. %A Fainzilber, Mike %D 2009 %J Neuron %K Animals; Apoptosis, Carrier Cell Cells, Cells; Cultured; Death, Factor, Growth Humans; Line; Medulloblastoma, Mice; Microfilament Mutation; Nerve Neuroblastoma, PC12 Prognosis; Proteins, Rats; Receptor, diagnosis/physiopathology; genetics/metabolism genetics/metabolism; metabolism; physiology; physiopathology; trkA, trkB, %N 5 %P 585--591 %R 10.1016/j.neuron.2009.08.020 %T CCM2 mediates death signaling by the TrkA receptor tyrosine kinase. %U http://dx.doi.org/10.1016/j.neuron.2009.08.020 %V 63 %X 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.

@article{harel2009mediates, __markedentry = {[bbrors:6]}, 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.}, added-at = {2015-04-09T12:36:21.000+0200}, author = {Harel, Liraz and Costa, Barbara and Tcherpakov, Marianna and Zapatka, Marc and Oberthuer, Andre and Hansford, Loen M. and Vojvodic, Milijana and Levy, Zehava and Chen, Zhe-Yu and Lee, Francis S. and Avigad, Smadar and Yaniv, Isaac and Shi, Leming and Eils, Roland and Fischer, Matthias and Brors, Benedikt and Kaplan, David R. and Fainzilber, Mike}, biburl = {https://www.bibsonomy.org/bibtex/219e70a6780bb7cf99f3e6de7cc5bc50c/bbrors}, doi = {10.1016/j.neuron.2009.08.020}, institution = {Department of Biological Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel.}, interhash = {5a4bcd47a00655e96131d0b27a599266}, intrahash = {19e70a6780bb7cf99f3e6de7cc5bc50c}, journal = {Neuron}, keywords = {Animals; Apoptosis, Carrier Cell Cells, Cells; Cultured; Death, Factor, Growth Humans; Line; Medulloblastoma, Mice; Microfilament Mutation; Nerve Neuroblastoma, PC12 Prognosis; Proteins, Rats; Receptor, diagnosis/physiopathology; genetics/metabolism genetics/metabolism; metabolism; physiology; physiopathology; trkA, trkB,}, language = {eng}, medline-pst = {ppublish}, month = Sep, number = 5, owner = {bbrors}, pages = {585--591}, pii = {S0896-6273(09)00632-1}, pmid = {19755102}, timestamp = {2015-04-09T12:36:21.000+0200}, title = {CCM2 mediates death signaling by the TrkA receptor tyrosine kinase.}, url = {http://dx.doi.org/10.1016/j.neuron.2009.08.020}, volume = 63, year = 2009 }