SH3 domain of spectrin participates in the activation of Rac in specialized calpain-induced integrin signaling complexes.
In this study, we used cultured cells spreading on beta3 integrin substrates to examine the possibility that spectrin is involved in signal transduction. Spectrin clustered with specialized calpain-induced beta3 integrin signaling complexes that mediate the initial attachment of cells and initiate Rac activation and lamellipodia extension. It was absent from focal complexes and focal adhesions, the integrin complexes that mediate adhesion in lamellipodia and fully spread cells. Spectrin contains a Src homology (SH3) domain of unknown function. Cells overexpressing this domain adhered and calpain-induced integrin signaling complexes formed. However, Rac activation, lamellipodia extension and cell spreading were inhibited. Spreading was restored by overexpression of constitutively active Rac. These studies point to a previously unrecognized role for spectrin and its SH3 domain in initiating Rac activation in the specialized integrin clusters that initiate cell adhesion and spreading. Thus, spectrin may have a pivotal role in initiating integrin-induced physiological and pathological events such as development, proliferation, cell survival, wound healing, metastasis and atherosclerosis.
Bialkowska
Katarzyna
K
Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Saido
Takaomi C
TC
Fox
Joan E B
JE
D000818:Animals; D001011:Aorta; D002154:Calpain / Q000502:physiology*; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D006801:Humans; D039661:Integrin beta3 / Q000502:physiology*; D011554:Pseudopodia / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013049:Spectrin / Q000737:chemistry / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D018909:src Homology Domains
D039661:Integrin beta3; D013049:Spectrin; D002154:Calpain; D020744:rac GTP-Binding Proteins