10779/crick.12683654.v1
Nicole A Gabreski
Nicole A
Gabreski
Janki K Vaghasia
Janki K
Vaghasia
Silvia S Novakova
Silvia S
Novakova
Neil Q McDonald
Neil Q
McDonald
Brian A Pierchala
Brian A
Pierchala
Exon skipping in RET gene encodes novel isoforms that differentially regulate RET protein signal transduction
The Francis Crick Institute
2020
alternative splicing
cell signaling
neurotrophic factor
receptor tyrosine kinase
signal transduction
Animals
Exons
Humans
Isoenzymes
Mice
NIH 3T3 Cells
Phosphorylation
Proto-Oncogene Proteins c-ret
Rats
Signal Transduction
Zebrafish
Zebrafish Proteins
McDonald FC001115
Biochemistry & Molecular Biology
06 Biological Sciences
11 Medical and Health Sciences
03 Chemical Sciences
2020-07-27 11:20:01
Journal contribution
https://crick.figshare.com/articles/journal_contribution/Exon_skipping_in_RET_gene_encodes_novel_isoforms_that_differentially_regulate_RET_protein_signal_transduction/12683654
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(Δ) (E3) and RET(Δ) (E345), respectively. Here we report the presence of Ret(Δ) (E3) and Ret(Δ) (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(ΔE3) and RET(ΔE345) 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, 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.