Published 26 November 2001. doi:10.1083/jcb.200106139
© The Rockefeller University Press,
0021-9525/2001/11/809 $5.00
The Journal of Cell Biology, Volume 155, Number 5, November 26, 2001 809-820
Direct interaction of insulin-like growth factor-1 receptor with leukemia-associated RhoGEF
Shinichiro Taya1,
Naoyuki Inagaki2,3,
Hiroaki Sengiku2,
Hiroshi Makino1,2,
Akihiro Iwamatsu4,
Itaru Urakawa4,
Kenji Nagao5,
Shiro Kataoka5 and
Kozo Kaibuchi1
1 Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, Showa-ku, Nagoya 466-8550, Japan
2 Division of Signal Transduction, Nara Institute of Science and Technology, Ikoma 630-0101, Japan
3 Recognition and Formation, PREST, JST, Kumamoto 860-0012, Japan
4 Central Laboratories for Key Technology, Kirin Brewery Company Limited, Kanazawa-ku, Yokohama 236-0004, Japan
5 Pharmaceutical Research Laboratory, Kirin Brewery Company Limited, Takasaki 370-1295, Japan
Address correspondence to Kozo Kaibuchi, Dept. of Cell Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan. Tel.: 81-52-744-2074. Fax: 81-52-744-2083. E-mail: kaibuchi{at}med.nagoya-u.ac.jp
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.
Key Words: IGF-1; Rho; LARG; PDZ domain; GEF
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