Essential role of Hrs in endocytic recycling of full-length TrkB receptor but not its isoform TrkB.T1.

Brain-derived neurotrophic factor (BDNF) signaling through its receptor, TrkB, modulates survival, differentiation, and synaptic activity of neurons. Both full-length TrkB (TrkB-FL) and its isoform T1 (TrkB.T1) receptors are expressed in neurons; however, whether they follow the same endocytic pathway after BDNF treatment is not known. In this study we report that TrkB-FL and TrkB.T1 receptors traverse divergent endocytic pathways after binding to BDNF. We provide evidence that in neurons TrkB.T1 receptors predominantly recycle back to the cell surface by a "default" mechanism. However, endocytosed TrkB-FL receptors recycle to a lesser extent in a hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs)-dependent manner which relies on its tyrosine kinase activity. The distinct role of Hrs in promoting recycling of internalized TrkB-FL receptors is independent of its ubiquitin-interacting motif. Moreover, Hrs-sensitive TrkB-FL recycling plays a role in BDNF-induced prolonged mitogen-activated protein kinase (MAPK) activation. These observations provide evidence for differential postendocytic sorting of TrkB-FL and TrkB.T1 receptors to alternate intracellular pathways.