title: Deficiency of Rap1-binding protein RAPL causes lymphoproliferative disorders through mislocalization of p27kip1.
abstract: RAPL (an alternative spliced form of Rassf5) is a critical Ras-related protein1 (Rap1) effector that regulates lymphocyte adhesion. Here, we have shown that in addition to this previously described function, RAPL also negatively controls lymphocyte proliferation and prevents autoimmunity and lymphoma. RAPL-deficient mice experienced age-related lupus-like glomerulonephritis and developed B cell lymphomas. RAPL-deficient lymphocytes showed hyperproliferation by enhanced S phase entry after antigen receptor ligation. Compared to wild-type cells, RAPL-deficient naive lymphocytes had a 2- to 3-fold increase in Cdk2 kinase activity with a cytoplasmic mislocalization of the cyclin-dependent kinase inhibitor p27(kip1). RAPL was found to suppress the phosphorylation of p27(kip1) on serine 10 (S10) and promoted p27(kip1) nuclear translocation. An S10A mutation in p27(kip1) corrected its cytoplasmic accumulation, reduced hyperproliferation in RAPL-deficient lymphocytes, and suppressed glomerulonephritis and development of B cell lymphoma. Thus, RAPL serves as a checkpoint for S phase entry to prevent lymphoproliferative disorders through the spatial regulation of p27(kip1).
authors.affiliation: Department of Life Science, School of Science and Technology, Kwanseigakuen University, and JST, CREST, 2-1 Gakuen, Sanda, Hyogo 669-1337, Japan.
authors.forename: Koko
authors.initials: K
authors.lastname: Katagiri
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ueda
authors.forename: Takashi
authors.initials: T
authors.lastname: Tomiyama
authors.forename: Kaneki
authors.initials: K
authors.lastname: Yasuda
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Toda
authors.forename: Susumu
authors.initials: S
authors.lastname: Ikehara
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kinashi
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008232:Lymphoproliferative Disorders / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D020827:rap1 GTP-Binding Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins
chemical_list: D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D020827:rap1 GTP-Binding Proteins; C455831:Rassf5 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins