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

Shinichiro Taya, Naoyuki Inagaki, Hiroaki Sengiku, Hiroshi Makino, Akihiro Iwamatsu, Itaru Urakawa, Kenji Nagao, Shiro Kataoka, Kozo Kaibuchi

Research output: Contribution to journalArticlepeer-review

93 Citations (Scopus)

Abstract

Insulin-like growth factor (IGF)-1 plays crucial roles in growth control and rearrangements of the cytoskeleton. IGF-1 binds to the IGF-1 receptor and thereby induces the autophosphorylation of this receptor at its tyrosine residues. The phosphorylation of the IGF-1 receptor is thought to initiate a cascade of events. Although various signaling molecules have been identified, they appear to interact with the tyrosine-phosphorylated IGF-1 receptor. Here, we identified leukemia-associated Rho guanine nucleotide exchange factor (GEF) (LARG), which contains the PSD-95/Dlg/ZO-1 (PDZ), regulator of G protein signaling (RGS), Dbl homology, and pleckstrin homology domains, as a nonphosphorylated IGF-1 receptor- interacting molecule. LARG formed a complex with the IGF-1 receptor in vivo, and the PDZ domain of LARG interacted directly with the COOH-terminal domain of IGF-1 receptor in vitro. LARG had an exchange activity for Rho in vitro and induced the formation of stress fibers in NIH 3T3 fibroblasts. When MDCKII epithelial cells were treated with IGF-1, Rho and its effector Rho-associated kinase (Rho-kinase) were activated and actin stress fibers were enhanced. Furthermore, the IGF-1-induced Rho-kinase activation and the enhancement of stress fibers were inhibited 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 rearrangements.

Original languageEnglish
Pages (from-to)809-819
Number of pages11
JournalJournal of Cell Biology
Volume155
Issue number5
DOIs
Publication statusPublished - 26-11-2001
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cell Biology

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