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

Barbara Costa,Michelle J Kean,Volker Ast,James D.R Knight,Alice Mett,Zehava Levy,Derek F Ceccarelli,Beatriz Gonzalez Badillo,Roland Eils,Rainer König,Anne-Claude Gingras,Mike Fainzilber

doi:10.1074/jbc.c112.345397

Abstract

The TrkA receptor tyrosine kinase induces death in medulloblastoma cells via an interaction with the cerebral cavernous malformation 2 (CCM2) protein. We used 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.

Highlights

The cytoplasmic adaptor protein cerebral cavernous malformation 2 (CCM2) interacts with the TrkA receptor tyrosine kinase to induce pediatric tumor cell death
In addition to the previously reported interactors CCM1, CCM3, and ICAP1 [6], we found CCM2 or its subdomains interacting with MST4, STK24, and STK25, all members of the germinal center kinase class III (GCKIII) family
We have previously shown that CCM2 is a cytoplasmic interactor of TrkA that is necessary for NGF-induced cell death in pediatric tumor cells [4]

Summary

Background

The cytoplasmic adaptor protein CCM2 interacts with the TrkA receptor tyrosine kinase to induce pediatric tumor cell death. The Trk family of neurotrophin receptors are critical regulators of cell survival in the nervous system [1], but paradoxically, TrkA has been reported to induce cell death in pediatric tumor cells of neural origin [2] 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]. 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]. We describe a proteomics screen for interactors of the Karet domain of CCM2, leading to identification of STK25 as an effector of death signaling initiated by TrkA and CCM2

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION