A kinase-deficient TrkC receptor isoform activates Arf6–Rac1 signaling through the scaffold protein tamalin

Abstract

Neurotrophins play an essential role in mammalian development. Most of their functions have been attributed to activation of the kinase-active Trk receptors and the p75 neurotrophin receptor. Truncated Trk receptor isoforms lacking the kinase domain are abundantly expressed during development and in the adult; however, their function and signaling capacity is largely unknown. We show that the neurotrophin-3 (NT3) TrkCT1-truncated receptor binds to the scaffold protein tamalin in a ligand-dependent manner. Moreover, NT3 initiation of this complex leads to activation of the Rac1 GTPase through adenosine diphosphate-ribosylation factor 6 (Arf6). At the cellular level, NT3 binding to TrkCT1–tamalin induces Arf6 translocation to the membrane, which in turn causes membrane ruffling and the formation of cellular protrusions. Thus, our data identify a new signaling pathway elicited by the kinase-deficient TrkCT1 receptor. Moreover, we establish NT3 as an upstream regulator of Arf6.

Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders

“…Regulatory regions at 3'UTRs have been poorly studied in the past and information about their genetic variation is almost non-existent. This definitely applies to the truncated isoform of NTRK3, for which very little is known and it has only recently been demonstrated to activate a specific signalling pathway [Esteban, et al, 2006]. The lack of SNPs in the 3'UTRs of NTRK3 in public databases could be explained by a stronger action of negative selection on these regions in comparison to other non-coding regions.…”

Neurotrophin receptors: Old friends with new partners

“…However, the truncated TrkB and TrkC isoforms also have the capacity to directly mediate neurotrophin-dependent signaling. NT-3 acting on truncated isoform TrkC.T1 activates Rac1 through association with a scaffold protein, tamalin (Esteban et al, 2006) and promotes neural crest cell proliferation and neuronal differentiation via a signaling pathway that requires the participation of p75 NTR (Hapner et al, 1998). Similarly, BDNF binding-truncated isoform TrkB.T1 regulates formation of dendritic filopodia in hippocampal neurons, via a complex with p75 NTR (Hartmann et al, 2004).…”

Ethanol–BDNF interactions: Still more questions than answers

“…The truncated TrkB and TrkC isoforms do not activate these pathways but decrease full-length Trk receptor activation (Eide et al, 1996) and signal through G-proteins to increase intracellular calcium (Rose et al, 2003). TrkB.T1 increases filopodia formation (Hartmann et al, 2004) and truncated TrkC can signal through PSD-95 to increase membrane ruffling (Esteban et al, 2006). Activation of signal transduction cascades by TrkB leads to expression and/or phosphorylation of multiple transcription factors.…”