Involvement of IQGAP3, a regulator of Ras/ERK-related cascade, in hepatocyte proliferation in mouse liver regeneration and development.
The spatio-temporal regulation of hepatocyte proliferation is a critical issue in liver regeneration. Here, in normal and regenerating liver as well as in developing liver, we examined its expression/localization of IQGAP3, which was most recently reported as a Ras/Rac/Cdc42-binding proliferation factor associated with cell-cell contacts in epithelial-type cells. In parallel, the expression/localization of Rac/Cdc42-binding IQGAP1/2 was examined. IQGAP3 showed a specific expression in proliferating hepatocytes positive for the proliferating marker Ki-67, the levels of expressions of mRNAs and proteins were significantly increased in hepatocytes in liver regeneration and development. In immunofluorescence, IQGAP3 was highly enriched at cell-cell contacts of hepatocytes. IQGAP1 and IQGAP2 were exclusively expressed in Kupffer and sinusoidal endothelial cells, respectively, in normal, regenerating, and developing liver. The expression of IQGAP1, but not of IQGAP2, was increased in CCl4-induced (but not in partial hepatectomy-induced) liver regeneration. Exclusive expression/localization of IQGAP3 to hepatocytes in the liver likely reflects the specific involvement of the IQGAP3/Ras/ERK signaling cascade in hepatocyte proliferation in addition to the previously identified signaling pathways, possibly by integrating cell-cell contact-related proliferating signaling events. On the other hand, the Rac/Cdc42-binding properties of IQGAP1/2/3 may be related to the distinct modes of remodeling due to the different strategies which induced proliferation of liver cells; partial hepatectomy, CCl4 injury, or embryonic development. Thus, the functional orchestration of Ras and the Ras homologous (Rho) family proteins Rac/Cdc42 likely plays a critical role in liver regeneration and development.
Kunimoto
Koshi
K
Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Nojima
Hisashi
H
Yamazaki
Yuji
Y
Yoshikawa
Toshikazu
T
Okanoue
Takeshi
T
Tsukita
Sachiko
S
D000818:Animals; D002251:Carbon Tetrachloride; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006498:Hepatectomy; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D007728:Kupffer Cells / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development / Q000601:surgery; D008107:Liver Diseases / Q000201:enzymology* / Q000503:physiopathology; D008115:Liver Regeneration / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
D020690:GTPase-Activating Proteins; C101203:IQ motif containing GTPase activating protein 1; C531126:IQGAP3 protein, mouse; C484416:Iqgap2 protein, mouse; D012333:RNA, Messenger; D020703:ras GTPase-Activating Proteins; D002251:Carbon Tetrachloride; D048049:Extracellular Signal-Regulated MAP Kinases; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D018631:ras Proteins