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Published online 5 February 2001. doi:10.1083/jcb.152.3.579
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© The Rockefeller University Press, 0021-9525/2001/2/579/ $5.00
The Journal of Cell Biology, Volume 152, Number 3, February 5, 2001 579-594

Original Article

Cdc42Hs Facilitates Cytoskeletal Reorganization and Neurite Outgrowth by Localizing the 58-kD Insulin Receptor Substrate to Filamentous Actin

Sheila Govinda, Robert Kozmaa,b, Clinton Monfriesa,b, Louis Lima,b, and Sohail Ahmeda,b
a Department of Neurochemistry, Institute of Neurology, London WC1N 1PJ, United Kingdom
b Glaxo-IMCB Group, Institute of Molecular and Cell Biology, Singapore 119076

Correspondence to: Sohail Ahmed, Department of Neurochemistry, Institute of Neurology, 1 Wakefield St., London WC1N 1PJ, UK. Tel:44-020-7278-1552 Fax:44-020-7278-7045 E-mail:s.ahmed{at}ion.ucl.ac.uk.

Cdc42Hs is involved in cytoskeletal reorganization and is required for neurite outgrowth in N1E-115 cells. To investigate the molecular mechanism by which Cdc42Hs regulates these processes, a search for novel Cdc42Hs protein partners was undertaken by yeast two-hybrid assay. Here, we identify the 58-kD substrate of the insulin receptor tyrosine kinase (IRS-58) as a Cdc42Hs target. IRS-58 is a brain-enriched protein comprising at least four protein–protein interaction sites: a Cdc42Hs binding site, an Src homology (SH)3-binding site, an SH3 domain, and a tryptophan, tyrptophan (WW)-binding domain. Expression of IRS-58 in Swiss 3T3 cells leads to reorganization of the filamentous (F)-actin cytoskeleton, involving loss of stress fibers and formation of filopodia and clusters. In N1E-115 cells IRS-58 induces neurite outgrowth with high complexity. Expression of a deletion mutant of IRS-58, which lacks the SH3- and WW-binding domains, induced neurite extension without complexity in N1E-115 cells. In Swiss 3T3 cells and N1E-115 cells, IRS-58 colocalizes with F-actin in clusters and filopodia. An IRS-581267N mutant unable to bind Cdc42Hs failed to localize with F-actin to induce neurite outgrowth or significant cytoskeletal reorganization. These results suggest that Cdc42Hs facilitates cytoskeletal reorganization and neurite outgrowth by localizing protein complexes via adaptor proteins such as IRS-58 to F-actin.

Key Words: Cdc42Hs, F-actin, filopodia, neurite outgrowth, cytoskeleton


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