Figure 9.

Proposed model for how GIV regulates integrin signaling in cancer cells. Invasive cancer cells express more GIV than noninvasive cancer cells or nontransformed cells (Ghosh et al., 2010; Garcia-Marcos et al., 2011b), which leads to amplification of signals from GPCRs, RTKs, and integrins (this work). This amplification of signals from integrins (as well as from the other receptors) promotes the remodeling of the actin cytoskeleton, cell motility, and invasion. Mechanistically, GIV binds directly to integrin cytoplasmic tails upon ECM stimulation and is required to recruit Gαi3 to active integrin complexes. Activation of Gαi by GIV triggers the release of free Gβγ, which in turn activates PI3K. This GIV–Gαi–Gβγ–PI3K axis works in parallel to previously described mechanisms of PI3K activation by integrins (Legate et al., 2009), resulting in the enhanced response observed in invasive cancer cells with up-regulated GIV.