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Signal-Transducing Adaptor Protein-2 Regulates Integrin-Mediated T Cell Adhesion through Protein Degradation of Focal Adhesion Kinase¹

Yuichi Sekine^2,*, Satoshi Tsuji^2,*, Osamu Ikeda^*, Kenji Sugiyma, Kenji Oritani, Kazuya Shimoda, Ryuta Muromoto^*, Norihiko Ohbayashi^*, Akihiko Yoshimura^¶ and Tadashi Matsuda^3,*

^* Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan; Nippon Boehringer Ingelheim, Kawanishi Pharma Research Institute, Hyogo, Japan; Department of Hematology and Oncology, Graduate School of Medicine, Osaka University, Osaka, Japan; Department of Internal Medicine II, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; and ^¶ Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

Signal-transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that contains pleckstrin homology- and Src homology 2-like domains as well as a YXXQ motif in its C-terminal region. Our previous studies demonstrated that STAP-2 binds to STAT3 and STAT5, and regulates their signaling pathways. In the present study, we find that STAP-2-deficient splenocytes or T cells exhibit enhanced cell adhesion to fibronectin after PMA treatment, and that STAP-2-deficient T cells contain the increased protein contents of focal adhesion kinase (FAK). Furthermore, overexpression of STAP-2 induces a dramatic decrease in the protein contents of FAK and integrin-mediated T cell adhesion to fibronectin in Jurkat T cells via the degradation of FAK. Regarding the mechanism for this effect, we found that STAP-2 associates with FAK and enhances its degradation, proteasome inhibitors block FAK degradation, and STAP-2 recruits an endogenous E3 ubiquitin ligase, Cbl, to FAK. These results reveal a novel regulation mechanism for integrin-mediated signaling in T cells via STAP-2, which directly interacts with and degrades FAK.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

² Y.S. and S.T. equally contributed to this work.

³ Address correspondence and reprint requests to Dr. Tadashi Matsuda, Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-Ku Kita 12 Nishi 6, Sapporo 060-0812, Japan. E-mail address: tmatsuda{at}pharm.hokudai.ac.jp

⁴ Abbreviations used in this paper: STAP-2, signal-transducing adaptor protein-2; FAK, focal adhesion kinase; FN, fibronectin; HA, hemagglutinin; PH, pleckstrin homology; SH2, Src homology 2; siRNA, small interfering RNA; WT, wild type.

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