TY - JOUR
T1 - The cytoskeletal adaptor protein IQGAP1 regulates TCR-mediated signaling and filamentous actin dynamics
AU - Gorman, Jacquelyn A.
AU - Babich, Alexander
AU - Dick, Christopher J.
AU - Schoon, Renee A.
AU - Koenig, Alexander
AU - Gomez, Timothy S.
AU - Burkhardt, Janis K.
AU - Billadeau, Daniel D.
PY - 2012/6/15
Y1 - 2012/6/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84862626038&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862626038&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1103487
DO - 10.4049/jimmunol.1103487
M3 - Article
C2 - 22573807
AN - SCOPUS:84862626038
SN - 0022-1767
VL - 188
SP - 6135
EP - 6144
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -