Exon Skipping in the RET Gene Encodes Novel Isoforms That Differentially Regulate RET Protein Signal Transduction.

ABSTRACT: Rearranged during transfection (RET), a receptor tyrosine kinase that is activated by the glial cell line-derived neurotrophic factor family ligands (GFLs), plays a crucial role in the development and function of the nervous system and additionally is required for kidney development and spermatogenesis. RET encodes a transmembrane receptor that is 20 exons long and produces two known protein isoforms differing in C-terminal amino acid composition, referred to as RET9 and RET51. Studies of human pheochromocytomas identified two additional novel transcripts involving the skipping of exon 3 or exons 3, 4, and 5 and are referred to as RET(?) (E3) and RET(?) (E345), respectively. Here we report the presence of Ret(?) (E3) and Ret(?) (E345) in zebrafish, mice, and rats and show that these transcripts are dynamically expressed throughout development of the CNS, peripheral nervous system, and kidneys. We further explore the biochemical properties of these isoforms, demonstrating that, like full-length RET, RET(?E3) and RET(?E345) are trafficked to the cell surface, interact with all four GFR? co-receptors, and have the ability to heterodimerize with full-length RET. Signaling experiments indicate that RET(?E3) is phosphorylated in a similar manner to full-length RET. RET(?E345), in contrast, displays higher baseline autophosphorylation, specifically on the catalytic tyrosine, Tyr(905), and also on one of the most important signaling residues, Tyr(1062) These data provide the first evidence for a physiologic role of these isoforms in RET pathway function.

SUBMITTER: Gabreski NA 

PROVIDER: S-EPMC4965573 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature