title: CD99 inhibits CD98-mediated β1 integrin signaling through SHP2-mediated FAK dephosphorylation.
abstract: The human CD99 protein is a 32-kDa type I transmembrane glycoprotein, while CD98 is a disulfide-linked 125-kDa heterodimeric type II transmembrane glycoprotein. It has been previously shown that CD99 and CD98 oppositely regulate β1 integrin signaling, though the mechanisms by which this regulation occurs are not known. Our results revealed that antibody-mediated crosslinking of CD98 induced FAK phosphorylation at Y397 and facilitated the formation of the protein kinase Cα (PKCα)-syntenin-focal adhesion kinase (FAK), focal adhesions (FAs), and IPP-Akt1-syntenin complex, which mediates β1 integrin signaling. In contrast, crosslinking of CD99 disrupted the formation of the PKCα-syntenin-FAK complex as well as FA via FAK dephosphorylation. The CD99-induced dephosphorylation of FAK was apparently mediated by the recruitment of Src homology region 2 domain-containing phosphatase-2 (SHP2) to the plasma membrane and subsequent activation of its phosphatase activity. Further consequences of the activation of SHP2 included the disruption of FAK-talin and talin-β1 integrin interactions and attenuation in the formation of the IPP-Akt1-syntenin complex at the plasma membrane, which resulted in reduced cell-ECM adhesion. This report uncovers the molecular mechanisms underlying the inverse regulation of β1 integrin signaling by CD99 and CD98 and may provide a novel therapeutic approach to treat inflammation and cancer.
authors.affiliation: Department of Anatomy and Cell Biology, School of Medicine, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Kyoung Jin
authors.initials: KJ
authors.lastname: Lee
authors.affiliation: Department of Anatomy and Cell Biology, School of Medicine, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Yeon Ho
authors.initials: YH
authors.lastname: Yoo
authors.affiliation: Department of Anatomy and Cell Biology, School of Medicine, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Min Seo
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Cell Biology, School of Medicine, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Birendra Kumar
authors.initials: BK
authors.lastname: Yadav
authors.affiliation: Department of Anatomy and Cell Biology, School of Medicine, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Cell Biology, School of Medicine, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Dongyoung
authors.initials: D
authors.lastname: Lim
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Cheol
authors.initials: C
authors.lastname: Hwangbo
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Moon
authors.affiliation: Department of Anatomy and Cell Biology, School of Medicine, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Daejoong
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Dooil
authors.initials: D
authors.lastname: Jeoung
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Hansoo
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Jeong-Hyung
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Anatomy and Cell Biology, School of Medicine, Kangwon National University, Chuncheon 200-701, Republic of Korea. Electronic address: jhahn@kangwon.ac.kr.
authors.forename: Jang-Hee
authors.initials: JH
authors.lastname: Hahn
mesh_terms: D000071443:12E7 Antigen; D015703:Antigens, CD / Q000378:metabolism*; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D022001:Focal Adhesions / Q000378:metabolism; D027261:Fusion Regulatory Protein-1 / Q000378:metabolism*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D053676:Syntenins / Q000378:metabolism
chemical_list: D000071443:12E7 Antigen; D015703:Antigens, CD; C061828:CD99 protein, human; D015815:Cell Adhesion Molecules; D027261:Fusion Regulatory Protein-1; D019012:Integrin beta1; D034741:RNA, Small Interfering; D053676:Syntenins; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
keywords: CD98; CD99; Cell–ECM adhesion; FAK; Inflammation and cancer; SHP2; β1 integrin