Signal-transducing adaptor protein-2 regulates integrin-mediated T cell adhesion through protein degradation of focal adhesion kinase.
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.
Sekine
Yuichi
Y
Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Tsuji
Satoshi
S
Ikeda
Osamu
O
Sugiyma
Kenji
K
Oritani
Kenji
K
Shimoda
Kazuya
K
Muromoto
Ryuta
R
Ohbayashi
Norihiko
N
Yoshimura
Akihiko
A
Matsuda
Tadashi
T
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D020816:Amino Acid Motifs / Q000235:genetics / Q000276:immunology; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D005353:Fibronectins / Q000276:immunology / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018909:src Homology Domains / Q000235:genetics / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D005353:Fibronectins; D016023:Integrins; D010750:Phosphoproteins; C413897:STAP2 protein, human; C523144:STAP2 protein, mouse; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494085:Stat2 protein, mouse; C494087:Stat3 protein, mouse; D050721:Proto-Oncogene Proteins c-cbl; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; D046988:Proteasome Endopeptidase Complex; C067419:CBL protein, human