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.
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Cover Image
Chakraborti and colleagues (pp. 1345–1362) report the identification of bacteriophage ƛ NinH as a structural and functional analog of the bacterial nucleoid-associated protein Fis. NinH may influence phage excision-integration reactions or bacterial gene expression by competing with Fis for binding sites. The cover image shows Fis bound to DNA with homology to NinH highlighted. NinH binds and bends DNA with a preference for a 15 bp palindromic motif that is closely related to that recognised by E. coli Fis.
Comparison of tyrosine kinase domain properties for the neurotrophin receptors TrkA and TrkB
Stephen C. Artim, Anatoly Kiyatkin, Mark A. Lemmon; Comparison of tyrosine kinase domain properties for the neurotrophin receptors TrkA and TrkB. Biochem J 30 October 2020; 477 (20): 4053–4070. doi: https://doi.org/10.1042/BCJ20200695
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