The TrkC receptor induces apoptosis when the dependence receptor notion meets the neurotrophin paradigm

Abstract

The TrkC/NT-3 receptor/ligand pair is believed to be part of the classic neurotrophic theory claiming that neuronal death occurs by default when neurotrophic factors become limited, through loss of survival signals. Here, we show that TrkC is a dependence receptor and, as such, induces caspase-dependent apoptotic death in the absence of NT-3 in immortalized cells, a proapoptotic activity inhibited by the presence of NT-3. This proapoptotic activity of TrkC relies on the caspase-mediated cleavage of the intracellular domain of TrkC, which permits the release of a proapoptotic fragment. This fragment induces apoptosis through a caspase-9-dependent mechanism. Finally, we show that the death of dorsal root ganglion (DRG) neurons provoked by NT-3 withdrawal is inhibited when TrkC-proapoptotic activity is antagonized. Thus, the death of neurons upon disappearance of NT-3 is not only due to a loss of survival signals but also to the active proapoptotic activity of the unbound TrkC dependence receptor.neurotrophin-3 ͉ sensory neurons ͉ programmed cell death ͉ tyrosine kinase

Dependence receptors: a new paradigm in cell signaling and cancer therapy

“…This is in agreement with the view that TrkC, contrary to TrkA and B, can trigger, when deprived of ligand, an active apoptotic signaling. A confirmation that TrkC apoptotic signaling controls the fate of sensory neurons is provided by an experience in which microinjection in sensory neurons of a mutated intracellular domain of TrkC, known to interfere with TrkC apoptotic function, dramatically enhanced survival of NT-3-deprived neurons (Tauszig-Delamasure et al, 2007).…”

“…However, in light of what was known about DRs, it was tempting to hypothesize that neurotrophin binding served also to block an active apoptotic signal from Trks. Interestingly, when Trk receptors were evaluated as possible DRs, TrkC was the only one the enforced expression of which induced cell death in the absence of ligand (Tauszig-Delamasure et al, 2007). Thus, TrkC is a DR, whereas TrkA and B are not, suggesting that even a closely related receptor can acquire a different activity with regard to cell survival and apoptosis ( Figure 2 and Table 1).…”

“…These receptors are named 'dependence receptors.' To date, the dependence receptor (DR) family is composed of more than a dozen members including DCC (deleted in colorectal carcinoma) (Mehlen et al, 1998), UNC5Hs (uncoordinated 5 homologs), neogenin (Matsunaga et al, 2004), p75 NTR (p75 neurotrophin receptor) (Rabizadeh et al, 1993), RET (rearranged during transfection) (Bordeaux et al, 2000), TrkC (tyrosine kinase receptor C) (Tauszig-Delamasure et al, 2007), Ptc (patched) (Thibert et al, 2003), EphA4 (ephrin type A receptor 4) (Furne et al, 2009), ALK (anaplastic lymphoma kinase) (Mourali et al, 2006), MET (Tulasne et al, 2004) and some integrins (Stupack et al, 2001). All of them are involved in both nervous system development and cancer progression.…”

Neurotrophins and B-cell malignancies

“…Truncated Trk receptors have been shown to bind to neurotrophins, particularly truncated TrkB (TrkB 95 ) to BDNF. TrkB has two truncated splice variants, TrkB 95 (also known as TrkB.T1) and TrkB.T2. It was initially thought that these receptors functioned purely as dominant negative receptors, through hetero-dimerisation with full length TrkB in neurons [72,73].…”

“…TrkC is known to have caspase cleavage sites in the intracellular domain, making it a more typical dependence receptor [95].…”