Abstract
The tropomyosin-related kinase (Trk) family consists of three receptor tyrosine kinases (RTKs) called TrkA, TrkB, and TrkC. These RTKs are regulated by the neurotrophins, a class of secreted growth factors responsible for the development and function of neurons. The Trks share a high degree of homology and utilize overlapping signaling pathways, yet their signaling is associated with starkly different outcomes in certain cancers. For example, in neuroblastoma, TrkA expression and signaling correlates with a favorable prognosis, whereas TrkB is associated with poor prognoses. To begin to understand how activation of the different Trks can lead to such distinct cellular outcomes, we investigated differences in kinase activity and duration of autophosphorylation for the TrkA and TrkB tyrosine kinase domains (TKDs). We find that the TrkA TKD has a catalytic efficiency that is ∼2-fold higher than that of TrkB, and becomes autophosphorylated in vitro more rapidly than the TrkB TKD. Studies with mutated TKD variants suggest that a crystallographic dimer seen in many TrkA (but not TrkB) TKD crystal structures, which involves the kinase-insert domain, may contribute to this enhanced TrkA autophosphorylation. Consistent with previous studies showing that cellular context determines whether TrkB signaling is sustained (promoting differentiation) or transient (promoting proliferation), we also find that TrkB signaling can be made more transient in PC12 cells by suppressing levels of p75NTR. Our findings shed new light on potential differences between TrkA and TrkB signaling, and suggest that subtle differences in signaling dynamics can lead to substantial shifts in the cellular outcome.
Highlights
The tropomyosin receptor kinase (Trk) family [1] comprises three receptor tyrosine kinases (RTKs) called TrkA, TrkB, and TrkC that are activated by neurotrophins
TrkA functions as the primary receptor for nerve growth factor (NGF), TrkB is the primary receptor for brainderived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4), and TrkC is the primary receptor for neurotrophin-3 (NT-3)
Several reports have demonstrated that TrkA and TrkB expression and activation can result in distinct cellular outcomes in the same cell type [4, 7, 58, 66]
Summary
The tropomyosin receptor kinase (Trk) family [1] comprises three receptor tyrosine kinases (RTKs) called TrkA, TrkB, and TrkC that are activated by neurotrophins. The Trks primarily regulate neuronal survival and differentiation through a highly complex set of tightly controlled cell-specific and receptorspecific interactions. They are associated with certain cancers, notably neuroblastoma, where the different receptors play starkly different roles [2, 3]. Activating TrkA signaling in neuroblastoma cells inhibits cell growth, whereas activation of TrkB does not [4]. Whereas TrkA expression and activation promotes cell differentiation and a favorable prognosis in neuroblastoma, TrkB expression and activation causes cell proliferation and is associated with a poor prognosis [2, 3, 5, 6]. How can two homologous RTKs, both thought to engage similar downstream signaling pathways, produce opposite cellular responses?
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