IQGAP1 selectively interacts with K-Ras but not with H-Ras and modulates K-Ras function.
K-Ras is frequently mutated and activated especially in pancreatic cancers. To analyze K-Ras function, we have searched for K-Ras interacting proteins and found IQ motif containing GTPase activating protein 1 (IQGAP1) as a novel K-Ras binding protein. IQGAP1 has been known as a scaffold protein for B-Raf, MEK1/2 and ERK1/2. Here we showed that IQGAP1 selectively formed a complex with K-Ras but not with H-Ras, and recruited B-Raf to K-Ras. We found that IQ motif region of IQGAP1 interacted with K-Ras. Both active and inactive K-Ras interacted with IQGAP1, and effector domain mutants of K-Ras also associated with IQGAP1, indicating that IQGAP1 interacts with K-Ras irrespective of Ras-effectors like B-Raf. We also found that overexpression or knock-down of IQGAP1 affected the interaction between K-Ras and B-Raf, and IQGAP1 overexpression increased ERK1/2 phosphorylation in K-Ras dependent manner in PANC1 cells. Our data suggest that IQGAP1 has a novel mechanism to modulate K-Ras pathway.
Oncology Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, Japan.
Hironori
H
Matsunaga
Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd., 1-16-13, Kitakasai, Edogawa-ku, Tokyo, Japan.
Kazuishi
K
Kubota
Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd., 1-16-13, Kitakasai, Edogawa-ku, Tokyo, Japan.
Tatsuya
T
Inoue
Frontier Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, Japan.
Fujio
F
Isono
Oncology Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, Japan; U3 Pharma GmbH, Fraunhoferstr. 22, Martinsried, Planegg, Germany. Electronic address: ando.osamu.jy@daiichisankyo.co.jp.
Osamu
O
Ando
D002460:Cell Line; D018274:Electroporation; D006801:Humans; D010190:Pancreatic Neoplasms / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D020703:ras GTPase-Activating Proteins / Q000378:metabolism*
C101203:IQ motif containing GTPase activating protein 1; D020703:ras GTPase-Activating Proteins; D016283:Proto-Oncogene Proteins p21(ras)
IQ motif containing GTPase activating protein 1; K-Ras; Pancreatic cancer