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.
Huang
Shu-Hong
SH
Department of Neurobiology, Key Laboratory of Medical Neurobiology, School of Medicine, Jinan, Shandong 250012, China.
Zhao
Ling
L
Sun
Zong-Peng
ZP
Li
Xue-Zhi
XZ
Geng
Zhao
Z
Zhang
Kai-Di
KD
Chao
Moses V
MV
Chen
Zhe-Yu
ZY
D020816:Amino Acid Motifs; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002460:Cell Line; D004705:Endocytosis / Q000187:drug effects; D056827:Endosomal Sorting Complexes Required for Transport; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D019208:Brain-Derived Neurotrophic Factor; D056827:Endosomal Sorting Complexes Required for Transport; D007527:Isoenzymes; D008024:Ligands; D010750:Phosphoproteins; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; D020813:Receptor, trkB; D020928:Mitogen-Activated Protein Kinases