Novel isoform of insulin receptor substrate p53/p58 is generated by alternative splicing in the CRIB/SH3-binding region

Insulin receptor substrate p53/p58 (IRSp53) is involved in cytoskeletal dynamics and is a candidate disease sensor in polyglutamine expansion neurodegeneration. It is widely expressed throughout the body, but its levels are dramatically elevated in forebrain regions. IRSp53 functions as a signal transducing adaptor between activated Rho family GTPases and their effectors. There are four known alternatively spliced isoforms of IRSp53 that vary by the identity of the T-terminal exon. We report here that there is a fifth alternatively spliced isoform, IRSp53-B, which lacks 40 amino acids abutting the CRIB/SH3 ((C) under bar dc42/(R) under bar ac-(i) under bar nteractive (b) under bar inding/(S) under bar rc (h) under bar omology (3) under bar)-binding site. We speculate that the novel form has an altered function related to the mechanism of autoinactivation. IRSp53-B has an odd history in the mammalian lineage, which may complicate the use of rodent models to study cytoskeletal reorganization.