title: Src homology 2-domain containing leukocyte-specific phosphoprotein of 76 kDa is mandatory for TCR-mediated inside-out signaling, but dispensable for CXCR4-mediated LFA-1 activation, adhesion, and migration of T cells.
abstract: Engagement of the TCR or of chemokine receptors such as CXCR4 induces adhesion and migration of T cells via so-called inside-out signaling pathways. The molecular processes underlying inside-out signaling events are as yet not completely understood. In this study, we show that TCR- and CXCR4-mediated activation of integrins critically depends on the membrane recruitment of the adhesion- and degranulation-promoting adapter protein (ADAP)/Src kinase-associated phosphoprotein of 55 kDa (SKAP55)/Rap1-interacting adapter protein (RIAM)/Rap1 module. We further demonstrate that the Src homology 2 domain containing leukocyte-specific phosphoprotein of 76 kDa (SLP76) is crucial for TCR-mediated inside-out signaling and T cell/APC interaction. Besides facilitating membrane recruitment of ADAP, SKAP55, and RIAM, SLP76 regulates TCR-mediated inside-out signaling by controlling the activation of Rap1 as well as Rac-mediated actin polymerization. Surprisingly, however, SLP76 is not mandatory for CXCR4-mediated inside-out signaling. Indeed, both CXCR4-induced T cell adhesion and migration are not affected by loss of SLP76. Moreover, after CXCR4 stimulation, the ADAP/SKAP55/RIAM/Rap1 module is recruited to the plasma membrane independently of SLP76. Collectively, our data indicate a differential requirement for SLP76 in TCR- vs CXCR4-mediated inside-out signaling pathways regulating T cell adhesion and migration.
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Horn
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Wang
authors.forename: Peter
authors.initials: P
authors.lastname: Reichardt
authors.forename: Theresia E
authors.initials: TE
authors.lastname: Stradal
authors.forename: Nicole
authors.initials: N
authors.lastname: Warnecke
authors.forename: Luca
authors.initials: L
authors.lastname: Simeoni
authors.forename: Matthias
authors.initials: M
authors.lastname: Gunzer
authors.forename: Deborah
authors.initials: D
authors.lastname: Yablonski
authors.forename: Burkhart
authors.initials: B
authors.lastname: Schraven
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kliche
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology*; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D016169:Lymphocyte Function-Associated Antigen-1; D010750:Phosphoproteins; D019718:Receptors, CXCR4; C092947:SLP-76 signal Transducing adaptor proteins; D051193:Toll-Like Receptors