title: PLK1 and β-TrCP-dependent ubiquitination and degradation of Rap1GAP controls cell proliferation.
abstract: Rap1GAP is a GTPase-activating protein (GAP) that specifically stimulates the GTP hydrolysis of Rap1 GTPase. Although Rap1GAP is recognized as a tumor suppressor gene and downregulated in various cancers, little is known regarding the regulation of Rap1GAP ubiquitination and degradation under physiological conditions. Here, we demonstrated that Rap1GAP is ubiquitinated and degraded through proteasome pathway in mitosis. Proteolysis of Rap1GAP requires the PLK1 kinase and β-TrCP ubiquitin ligase complex. We revealed that PLK1 interacts with Rap1GAP in vivo through recognition of an SSP motif within Rap1GAP. PLK1 phosphorylates Ser525 in conserved 524DSGHVS529 degron of Rap1GAP and promotes its interaction with β-TrCP. We also showed that Rap1GAP was a cell cycle regulator and that tight regulation of the Rap1GAP degradation in mitosis is required for cell proliferation.
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, P.R. China; Department of Gastroenterology, Jiangxi Institute of Gastroenterology & Hepatology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, P. R. China.
authors.forename: Dejie
authors.initials: D
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, P.R. China; Institutes of Biomedical Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Pingzhao
authors.initials: P
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Kun
authors.initials: K
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Lymphoma and Myeloma, Division of Cancer Medicine, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yi
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Chenji
authors.initials: C
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, P.R. China; Institutes of Biomedical Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Long
authors.initials: L
authors.lastname: Yu
mesh_terms: D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D020690:GTPase-Activating Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D044844:beta-Transducin Repeat-Containing Proteins; D000097869:Polo-Like Kinase 1; C484658:RAP1GAP protein, human