On the death Trk.

The trk family of receptor tyrosine kinases supports survival and differentiation in the nervous system. Paradoxically it has also been shown that members of the trk family can induce cell death in pediatric tumor cells of neuronal origin. Moreover, TrkA and TrkC serve as good prognostic indicators in neuroblastoma and medulloblatoma, respectively. Although the possible linkage between these observations was intriguing, until recently there was limited insight on the mechanisms involved. Recent findings suggest that TrkA might influence neuronal cell death through stimulation of p75 cleavage. An alternative p75-independent mechanism was suggested by a newly discovered interaction between TrkA and CCM2 (the protein product of the gene cerebral cavernous malformation 2). Coexpression of CCM2 with TrkA induces cell death in medulloblastoma and neuroblastoma cells, and CCM2 expression levels correlate with those of TrkA and with good prognosis in neuroblastoma patients. Thus, mechanistic clues to the enigma of trk-induced cell death have begun to emerge. Detailed elucidation of these mechanisms and their in vivo physiological significance will be of keen interest for future research.