title: Actin polymerization-dependent activation of Cas-L promotes immunological synapse stability.
abstract: The immunological synapse formed between a T-cell and an antigen-presenting cell is important for cell-cell communication during T-cell-mediated immune responses. Immunological synapse formation begins with stimulation of the T-cell receptor (TCR). TCR microclusters are assembled and transported to the center of the immunological synapse in an actin polymerization-dependent process. However, the physical link between TCR and actin remains elusive. Here we show that lymphocyte-specific Crk-associated substrate (Cas-L), a member of a force sensing protein family, is required for transport of TCR microclusters and for establishing synapse stability. We found that Cas-L is phosphorylated at TCR microclusters in an actin polymerization-dependent fashion. Furthermore, Cas-L participates in a positive feedback loop leading to amplification of Ca2+signaling, inside-out integrin activation, and actomyosin contraction. We propose a new role for Cas-L in T-cell activation as a mechanical transducer linking TCR microclusters to the underlying actin network and coordinating multiple actin-dependent structures in the immunological synapse. Our studies highlight the importance of mechanotransduction processes in T-cell-mediated immune responses.
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY USA.|Skirball Institute of Biomolecular Medicine, New York School of Medicine, New York, NY USA.|Icahn Medical Institute, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Luís C
authors.initials: LC
authors.lastname: Santos
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York School of Medicine, New York, NY USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Blair
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York School of Medicine, New York, NY USA.
authors.forename: Sudha
authors.initials: S
authors.lastname: Kumari
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York School of Medicine, New York, NY USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Cammer
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Iskratsch
authors.affiliation: Icahn Medical Institute, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Herbin
authors.affiliation: Icahn Medical Institute, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Alexandropoulos
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York School of Medicine, New York, NY USA.|Kennedy Institute of Rheumatology, University of Oxford, Headington, UK.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Dustin
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Sheetz
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion; D050719:Crk-Associated Substrate Protein / Q000172:deficiency / Q000378:metabolism*; D054992:Immunological Synapses / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D010766:Phosphorylation; D058105:Polymerization; D021381:Protein Transport; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D000199:Actins; D050719:Crk-Associated Substrate Protein; D016023:Integrins; D011948:Receptors, Antigen, T-Cell; D002118:Calcium