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Expression of the human β3 integrin subunit in mouse smooth muscle cells enhances IGF‐I‐stimulated signaling and proliferation

Optimal stimulation of signal transduction and biological functions by IGF‐I in porcine smooth muscle cells (pSMC) requires ligand occupancy of the αVβ3 integrin. Binding of heparin‐binding domain (HBD) of vitronectin (VN) to the cysteine loop (C‐loop) region of β3 is required for pSMC to respond optimally to IGF‐I stimulation. Mouse smooth muscle cells (mSMC), which express a form of β3 whose sequence within the C‐loop region is different than porcine or human β3, do not respond optimally to IGF‐I, and IGF‐I stimulated β3 and SHPS‐1 phosphorylation which are necessary for optimal IGF‐I signaling were undetectable. VN also had no effect on IGF‐I stimulated the cell proliferation. In contrast, when human β3 (hβ3) was introduced into mSMC, there was an enhanced VN binding in spite of an equivalent amount of total β3 expression, and IGF‐I‐dependent β3, and SHPS‐1 phosphorylation were detected. In addition, there was enhanced IGF‐I‐stimulated Shc association with SHPS‐1, Shc tyrosine phosphorylation, Shc and Grb2 association, and MAP kinase activation leading to increased cell proliferation. These enhancements could be further augmented by adding a peptide containing the HBD of VN. To determine if these changes were mediated by the C‐loop region of β3, an antibody that reacts with that region of β3 was utilized. The addition of the hβ3 C‐loop antibody abolished VN‐induced enhancement of IGF‐I signaling and IGF‐I‐stimulated cell proliferation. These results strongly support the conclusion that optimal SMC responsiveness to IGF‐I requires ligand interaction with the C‐loop domain of hβ3. J. Cell. Physiol. 214: 306–315, 2008. © 2007 Wiley‐Liss, Inc.