title: Identification of a key motif that determines the differential surface levels of RET and TrkB tyrosine kinase receptors and controls depolarization enhanced RET surface insertion.
abstract: The RET tyrosine kinase receptor plays an important role in the development and maintenance of the nervous system. Although the ligand-induced RET signaling pathway has been well described, little is known about the regulation of RET surface expression, which is integral to the cell ability to control the response to ligand stimuli. We found that in dorsal root ganglion (DRG) neurons, which co-express RET and TrkB, the receptor surface levels of RET are significantly higher than that of TrkB. Using a sequence substitution strategy, we identified a key motif (Box1), which is necessary and sufficient for the differential RET and TrkB surface levels. Furthermore, pharmacological and mutagenesis assays revealed that protein kinase C (PKC) and high K(+) depolarization increase RET surface levels through phosphorylation of the Thr(675) residue in the Box1 motif. Finally, we found that the phosphorylation status of the Thr(675) residue influences RET mediated response to GDNF stimulation. In all, these findings provide a novel mechanism for the modulation of RET surface expression.
authors: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong 250012, PR China.
authors: Xue-Zhi
authors: XZ
authors: Li
authors: Jing
authors: J
authors: Yan
authors: Shu-Hong
authors: SH
authors: Huang
authors: Ling
authors: L
authors: Zhao
authors: Jue
authors: J
authors: Wang
authors: Zhe-Yu
authors: ZY
authors: Chen
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002462:Cell Membrane / Q000201:enzymology / Q000235:genetics; D005727:Ganglia, Spinal / Q000166:cytology / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D016716:PC12 Cells; D010766:Phosphorylation / Q000502:physiology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D051096:Proto-Oncogene Proteins c-ret / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D051096:Proto-Oncogene Proteins c-ret; D020813:Receptor, trkB; C495001:Ret protein, rat; D011493:Protein Kinase C