ZFIN ID: ZDB-PUB-160527-3
Exon Skipping in RET Encodes Novel Isoforms that Differentially Regulate RET Signal Transduction
Gabreski, N.A., Vaghasia, J.K., Novakova, S.S., McDonald, N.Q., Pierchala, B.A.
Date: 2016
Source: The Journal of biological chemistry   291(31): 16249-62 (Journal)
Registered Authors:
Keywords: alternative splicing, cell signaling, neurotrophic factor, receptor tyrosine kinase, signal transduction
MeSH Terms:
  • Animals
  • Exons*
  • Humans
  • Isoenzymes/genetics
  • Isoenzymes/metabolism
  • Mice
  • NIH 3T3 Cells
  • Phosphorylation/physiology
  • Proto-Oncogene Proteins c-ret/genetics
  • Proto-Oncogene Proteins c-ret/metabolism*
  • Rats
  • Signal Transduction/physiology*
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 27226544 Full text @ J. Biol. Chem.
RET, a receptor tyrosine kinase that is activated by the glial cell line-derived neurotrophic factor (GDNF) 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(ΔE3) and RET(ΔE345), respectively. Here we report the presence of Ret(ΔE3) and Ret(ΔE345) in zebrafish, mice, and rats, and show that these transcripts are dynamically expressed throughout development of the CNS, PNS 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 GFRα co-receptors, and have the ability to heterodimerize with full-length RET. Signaling experiments indicate that RET(ΔE3) is phosphorylated in a similar manner to full-length RET. RET(ΔE345), in contrast, displays higher baseline autophosphorylation, specifically on the catalytic tyrosine, Tyr905, and also on one of the most important signaling residues, Tyr1062. These data provide the first evidence for a physiologic role of these isoforms in RET pathway function.