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.

STK25 Protein Mediates TrkA and CCM2 Protein-dependent Death in Pediatric Tumor Cells of Neural Origin

“…This atypical function of TrkA is still largely unknown and is of keen interest in light of the fact that high expression of TrkA is strongly correlated with positive prognosis in neuroblastoma patients (3). We recently identified the protein product of the cerebral cavernous malformation 2 (CCM2) gene as a cytoplasmic interactor of TrkA that mediates its death effects in neuroblastoma and medulloblastoma (4). CCM2 is one of three genes mutated in patients with cerebral cavernous malformations (CCM), 3 a common class of vascular malformations in the central nervous system (5).…”

“…The protein products of these three genes, CCM1, CCM2, and CCM3, interact with each other and with numerous other partners to form a diversity of complexes that may mediate diverse functions in different cell types (6). However, CCM2 was the only CCMrelated gene that could be linked to positive prognosis in neuroblastoma patients, in correlation with TrkA, suggesting that the signaling pathways mediating TrkA-CCM2 death signaling in cells of neural origin might be distinct from the pathways leading to CCM effects on the vasculature (2,4).…”

“…CCM2 is a cytoplasmic protein composed of two domains, an N-terminal phosphotyrosine binding (PTB) domain and a C-terminal region with no obvious structural homologies or known function, termed the Karet domain (4). CCM2 interacts with TrkA via its PTB domain, but the interacting epitope in TrkA lacks phosphorylatable residues, suggesting that CCM2 serves as an adaptor that links to downstream effectors rather than directly impacting on TrkA signaling.…”

Molecular and Genetic Basis of Cerebral Cavernous Malformations

“…Bunun aksine, CCM2 ve TrkA'nın kombine yüksek miktardaki ekspresyonunun nöroblastoma hücrelerini ölüme götürdüğü, hastalarda sağkalım süresini uzattığı gösterilmiştir. Bu bulgular CCM2-TrkA sinyalizasyonunun tümör gerilemesinde spesifik fonksiyonel bir rolü olabileceğini akıllara getirmektedir (34).…”

Unravelling the Mechanism of TrkA-Induced Cell Death by Macropinocytosis in Medulloblastoma Daoy Cells

“…In many instances, in both primary as well as established MED, NB, and glioblastoma (GB) cell lines, expression of either TrkA or TrkC has been linked to the induction of either apoptosis or autophagy (1,(9)(10)(11)(12). In contrast, we have shown that nerve growth factor (NGF) treatment of MED Daoy cells that overexpress TrkA (Daoy-TrkA) show a dramatic increase in uncontrolled macropinocytosis, causing catastrophic disintegration of cellular membrane integrity, which results in cell death (13).…”