title: The cytoskeletal adaptor protein IQGAP1 regulates TCR-mediated signaling and filamentous actin dynamics.
abstract: The Ras GTPase-activating-like protein IQGAP1 is a multimodular scaffold that controls signaling and cytoskeletal regulation in fibroblasts and epithelial cells. However, the functional role of IQGAP1 in T cell development, activation, and cytoskeletal regulation has not been investigated. In this study, we show that IQGAP1 is dispensable for thymocyte development as well as microtubule organizing center polarization and cytolytic function in CD8(+) T cells. However, IQGAP1-deficient CD8(+) T cells as well as Jurkat T cells suppressed for IQGAP1 were hyperresponsive, displaying increased IL-2 and IFN-γ production, heightened LCK activation, and augmented global phosphorylation kinetics after TCR ligation. In addition, IQGAP1-deficient T cells exhibited increased TCR-mediated F-actin assembly and amplified F-actin velocities during spreading. Moreover, we found that discrete regions of IQGAP1 regulated cellular activation and F-actin accumulation. Taken together, our data suggest that IQGAP1 acts as a dual negative regulator in T cells, limiting both TCR-mediated activation kinetics and F-actin dynamics via distinct mechanisms.
authors.affiliation: Department of Immunology, Schulze Center for Novel Therapeutics, College of Medicine, Mayo Clinic, Rochester, MN 55901, USA.
authors.forename: Jacquelyn A
authors.initials: JA
authors.lastname: Gorman
authors.forename: Alexander
authors.initials: A
authors.lastname: Babich
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Dick
authors.forename: Renee A
authors.initials: RA
authors.lastname: Schoon
authors.forename: Alexander
authors.initials: A
authors.lastname: Koenig
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Gomez
authors.forename: Janis K
authors.initials: JK
authors.lastname: Burkhardt
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000199:Actins / Q000276:immunology / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D003599:Cytoskeleton / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D014162:Transfection; D020703:ras GTPase-Activating Proteins / Q000276:immunology / Q000378:metabolism*
chemical_list: D000199:Actins; C101203:IQ motif containing GTPase activating protein 1; D011948:Receptors, Antigen, T-Cell; D020703:ras GTPase-Activating Proteins