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B Activation by the Adapter Protein ADAP1
* Department of Laboratory Medicine and Pathology and
Department of Medicine, Center for Immunology, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN, 55455
Following TCR stimulation, T cells utilize the hematopoietic specific adhesion and degranulation-promoting adapter protein (ADAP) to control both integrin adhesive function and NF-
B transcription factor activation. We have investigated the molecular basis by which ADAP controls these events in primary murine ADAP–/– T cells. Naive DO11.10/ADAP–/– T cells show impaired adhesion to OVAp (OVA aa 323–339)-bearing APCs that is restored following reconstitution with wild-type ADAP. Mutational analysis demonstrates that the central proline-rich domain and the C-terminal domain of ADAP are required for rescue of T:APC conjugate formation. The ADAP proline-rich domain is sufficient to bind and stabilize the expression of SKAP55 (Src kinase-associated phosphoprotein of 55 kDa), which is otherwise absent from ADAP–/– T cells. Interestingly, forced expression of SKAP55 in the absence of ADAP is insufficient to drive T:APC conjugate formation, demonstrating that both ADAP and SKAP55 are required for optimal LFA-1 function. Additionally, the ADAP proline-rich domain is required for optimal Ag-induced activation of CD69, CD25, and Bcl-xL, but is not required for assembly of the CARMA1/Bcl10/Malt1 (caspase-recruitment domain (CARD) membrane-associated guanylate kinase (MAGUK) protein 1/B-cell CLL-lymphoma 10/mucosa-associated lymphoid tissue lymphoma translocation protein 1) signaling complex and subsequent TCR-dependent NF-B activity. Our results indicate that ADAP is used downstream of TCR engagement to delineate two distinct molecular programs in which the ADAP/SKAP55 module is required for control of T:APC conjugate formation and functions independently of ADAP/CARMA1-mediated NF-B activation.
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1 Supported by National Institutes of Health Grants R01AI038474 (to Y.S.), R01AI031126 (to Y.S.), R01AI056016 (to E.J.P.), and T32DE007288 (to B.J.B.). Y.S. is supported in part by the Harry Kay Chair in Biomedical Research at the University of Minnesota.
2 Current address: R&D Systems, 614 McKinley Place NE, Minneapolis, MN 55413.
3 Address correspondence and reprint requests to Dr. Yoji Shimizu, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, MMC 334/Room 6-112 NHH, 312 Church Street SE, Minneapolis, MN 55455. E-mail address: shimi002{at}umn.edu
4 Abbreviations used in this paper: LAT, linker for activated T cells; ADAP, adhesion and degranulation-promoting adapter protein; Bcl10, B-cell CLL/lymphoma 10; CARMA1, caspase-recruitment domain (CARD) membrane-associated guanylate kinase (MAGUK) protein 1; CBM, CARMA1/Bcl10/Malt1; HA, hemagglutinin; hCAR, human coxsackievirus and adenovirus receptor; hSH3, helical SH3; KO, knockout; Malt1, mucosa-associated lymphoid tissue lymphoma translocation protein 1; OVAp, OVA aa 323–339; RIAM, Rap1-GTP-interacting adapter molecule; SH3, Src homology 3; SKAP55, Src kinase-associated phosphoprotein of 55 kDa; SLP-76, Src homology 2 domain-containing leukocyte-specific phosphoprotein of 76 kDa; WT, wild type; wtADAP, wild-type ADAP.
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