Direct interaction of insulin-like growth factor-1 receptor with leukemia-associated RhoGEF

Insulin-like growth factor (IGF)-1 plays crucial roles in growth control an d rearrangements of the cytoskeleton. IGF-1 binds to the IGF-1 receptor and thereby induces the autophosphorylation of this receptor at its tyrosine r esidues, The phosphorylation of the IGF-1 receptor is thought to initiate a cascade of events. Although various signaling molecules have been identifi ed, they appear to interact with the tyrosine-phosphorylated IGF-1 receptor . Here, we identified leukemia-associated Rho guanine nucleotide exchange f actor (GEF) (LARG), which contains the PSD-95/Dlg/ZO-1 (PDZ), regulator of G protein signaling (RGS), Dbl homology, and pleckstrin homology domains, a s a nonphosphorylated IGF-1 receptor-interacting molecule. LARG formed a co mplex with the IGF-1 receptor in vivo, and the PDZ domain of LARG interacte d directly with the COOH-terminal domain of IGF-1 receptor in vitro. LARG h ad an exchange activity for Rho in vitro and induced the formation of stres s fibers in NIH 3T3 fibroblasts. When MDCKII epithelial cells were treated with IGF-1, Rho and its effector Rho-associated kinase (Rho-kinase) were ac tivated and actin stress fibers were enhanced. Furthermore, the IGF-1-induc ed Rho-kinase activation and the enhancement of stress fibers were inhibite d by ectopic expression of the PDZ and RGS domains of LARG. Taken together, these results indicate that IGF-1 activates the Rho/Rho-kinase pathway via a LARG/IGF-1 receptor complex and thereby regulates cytoskeletal rearrange ments.