title: The N terminus of SKAP55 enables T cell adhesion to TCR and integrin ligands via distinct mechanisms.
abstract: The T cell receptor (TCR) triggers the assembly of "SLP-76 microclusters," which mediate signals required for T cell activation. In addition to regulating integrin activation, we show that Src kinase-associated phosphoprotein of 55 kD (SKAP55) is required for microcluster persistence and movement, junctional stabilization, and integrin-independent adhesion via the TCR. These functions require the dimerization of SKAP55 and its interaction with the adaptor adhesion and degranulation-promoting adaptor protein (ADAP). A "tandem dimer" containing two ADAP-binding SKAP55 Src homology 3 (SH3) domains stabilized SLP-76 microclusters and promoted T cell adhesion via the TCR, but could not support adhesion to integrin ligands. Finally, the SKAP55 dimerization motif (DM) enabled the coimmunoprecipitation of the Rap1-dependent integrin regulator Rap1-GTP-interacting adaptor molecule (RIAM), the recruitment of talin into TCR-induced adhesive junctions, and "inside-out" signaling to β1 integrins. Our data indicate that SKAP55 dimers stabilize SLP-76 microclusters, couple SLP-76 to the force-generating systems responsible for microcluster movement, and enable adhesion via the TCR by mechanisms independent of RIAM, talin, and β1 integrins.
authors.affiliation: Program in Immunology, Sackler School of Graduate Biomedical Sciences, and 2 Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA 02111.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ophir
authors.forename: Beiyun C
authors.initials: BC
authors.lastname: Liu
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Bunnell
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002448:Cell Adhesion; D019281:Dimerization; D006801:Humans; D016023:Integrins / Q000378:metabolism; D019169:Jurkat Cells; D008024:Ligands; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016023:Integrins; D008024:Ligands; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; C108336:SKAP1 protein, human; C092947:SLP-76 signal Transducing adaptor proteins