Cross-talk between integrin ?6?4 and insulin-like growth factor-1 receptor (IGF1R) through direct ?6?4 binding to IGF1 and subsequent ?6?4-IGF1-IGF1R ternary complex formation in anchorage-independent conditions.

ABSTRACT: Integrin ?v?3 plays a role in insulin-like growth factor-1 (IGF1) signaling (integrin-IGF1 receptor (IGF1R) cross-talk). The specifics of the cross-talk are, however, unclear. In a current model, "ligand occupancy" of ?v?3 (i.e. the binding of extracellular matrix proteins) enhances signaling induced by IGF1 binding to IGF1R. We recently reported that IGF1 directly binds to ?v?3 and induces ?v?3-IGF1-IGF1R ternary complex formation. Consistently, the integrin binding-defective IGF1 mutant (R36E/R37E) is defective in inducing ternary complex formation and IGF signaling, but it still binds to IGF1R. Like ?v?3, integrin ?6?4 is overexpressed in many cancers and is implicated in cancer progression. Here, we discovered that ?6?4 directly bound to IGF1, but not to R36E/R37E. Grafting the ?4 sequence WPNSDP (residues 167-172), which corresponds to the specificity loop of ?3, to integrin ?1 markedly enhanced IGF1 binding to ?1, suggesting that the WPNSDP sequence is involved in IGF1 recognition. WT IGF1 induced ?6?4-IGF1-IGF1R ternary complex formation, whereas R36E/R37E did not. When cells were attached to matrix, exogenous IGF1 or ?6?4 expression had little or no effect on intracellular signaling. When cell-matrix adhesion was reduced (in poly(2-hydroxyethyl methacrylate-coated plates), IGF1 induced intracellular signaling and enhanced cell survival in an ?6?4-dependent manner. Also IGF1 enhanced colony formation in soft agar in an ?6?4-dependent manner. These results suggest that IGF binding to ?6?4 plays a major role in IGF signaling in anchorage-independent conditions, which mimic the in vivo environment, and is a novel therapeutic target.

SUBMITTER: Fujita M 

PROVIDER: S-EPMC3320998 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature