title: Rich1 negatively regulates the epithelial cell cycle, proliferation and adhesion by CDC42/RAC1-PAK1-Erk1/2 pathway.
abstract: Rich1, a previously identified Rho GTPase-activating protein (RhoGAP), was found to have close relationship with Rho GTPase family members in multiple cellular processes in nervous cells and platelets. But the exact role of Rich1 in epithelial cells remains obscure. The present investigation demonstrated that up-regulation of Rich1 could cause S-phase arrest, proliferation inhibition and adhesion decline with F-actin amount decrease in epithelial cells. Further exploration in hepatocyte HL7702 revealed that overexpression of Rich1 could greatly elevate the intrinsic GTPase activities on both of CDC42 and RAC1 by stimulating GTP hydrolysis, which consequently attenuated the activities of the Rho proteins and the phosphorylation level of those in PAK1-ERK1/2 signaling cascade. While the GAP domain deleted Rich1 variant or silence of endogenous Rich1 expression could not result in any of the biological effects. It is indicated that Rich1, completely different from in other types of cells, might act as a crucial upstream negative regulator via its GAP domain in control of epithelial cell cycle, proliferation and focal adhesion through CDC42/RAC1-PAK1-ERK1/2 signaling pathway and F-actin dynamics.
authors.affiliation: Institute of Molecular Medicine and Oncology, Chongqing Medical University, Chongqing 400016, China. Electronic address: zhangjun1017@sohu.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Molecular Medicine and Oncology, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Molecular Medicine and Oncology, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Zhou
authors.affiliation: Chongqing Institute for Food and Drug Control, Chongqing 4001121, China.
authors.forename: Xue-Yi
authors.initials: XY
authors.lastname: Ren
authors.affiliation: Institute of Molecular Medicine and Oncology, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Lin
authors.affiliation: Institute of Molecular Medicine and Oncology, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Qian-Qing
authors.initials: QQ
authors.lastname: Zhang
authors.affiliation: Institute of Molecular Medicine and Oncology, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Yun-Hong
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Institute of Molecular Medicine and Oncology, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
mesh_terms: D002448:Cell Adhesion / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C504466:ARHGAP17 protein, human; D020690:GTPase-Activating Proteins; C107953:RAC1 protein, human; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein
keywords: CDC42; Cell proliferation; Focal adhesion; RAC1; Rich1; S-phase arrest