Gabreski, N.A. and Vaghasia, J.K. and Novakova, S.S. and McDonald, Neil Q. and Pierchala, B.A. (2016) Exon skipping in the RET Gene encodes novel isoforms that differentially regulate RET Protein signal transduction. Journal of Biological Chemistry 291 (31), pp. 16249-16262. ISSN 0021-9258.
|
Text
J. Biol. Chem.-2016-Gabreski-16249-62.pdf - Published Version of Record Download (3MB) | Preview |
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 RETΔE3 and RETΔE345, respectively. Here we report the presence of RetΔE3 and RetΔE345 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, RETΔE3 and RETΔE345 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 RETΔE3 is phosphorylated in a similar manner to full-length RET. RETΔE345, 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.
Metadata
| Item Type: | Article |
|---|---|
| Keyword(s) / Subject(s): | alternative splicing, cell signaling, neurotrophic factor, receptor tyrosine kinase, signal transduction |
| School: | Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences |
| Research Centres and Institutes: | Structural Molecular Biology, Institute of (ISMB) |
| Depositing User: | Neil Mcdonald |
| Date Deposited: | 29 Mar 2019 13:08 |
| Last Modified: | 02 Aug 2023 17:26 |
| URI: | https://eprints.bbk.ac.uk/id/eprint/16238 |
Statistics
Additional statistics are available via IRStats2.
Archive Staff Only (login required)
