Spatiotemporal organization of signaling events in lymphocytes are poorly understood. Ligands initiate multiple signaling pathways via unique receptors. Hundreds of signaling molecules take part in transducing complex membrane proximal events into meaningful cellular functions. Although exceptional progress has been made in the understanding of signaling molecules, the precise mechanisms that co-ordinate these factors remain an enigma. Scaffolding proteins have provided part of the explanation into how signaling events can be spatiotemporally coordinated. IQGAP1 is a 190 kDa cytoplasmic scaffolding protein. In this application, we propose to determine how the spacetime relativity of specific signaling events is controlled by IQGAP1. We hypothesize that IQGAP1 functions as a processing center to coordinate multiple signaling pathways. Through our preliminary work, we identify three major scaffolding functions for IQGAP1. First, IQGAP1 regulates ?-catenin/TCF/LEF activation pathway that is involved in the terminal maturation and subset specification of NK cells. Second, IQGAP1 forms a novel signalosome around the perinuclear region to regulate ERK1/2 activation via Rac1->Pak->Raf->MEK1/2 pathway. Third, IQGAP1 plays a central role in actin polymerization, microtubule elongation and MTOC formation, which are important for the immunological synapse formation, tumor lysis and cell movement. In this application, we propose to determine the precise mechanisms by which IQGAP1 mediates these scaffolding functions.
Spatiotemporal regulation of signaling cascades is poorly understood. Using a scaffold protein called IQGAP1, we propose to study the sequential signal transduction, signalosome formation, cytoskeletal remodeling and effector functions of NK cells.
|Arumugam, Vidhyalakshmi; Bluemn, Theresa; Wesley, Erin et al. (2015) TCR signaling intensity controls CD8+ T cell responsiveness to TGF-Î². J Leukoc Biol 98:703-12|
|Abel, Alex M; Schuldt, Kristina M; Rajasekaran, Kamalakannan et al. (2015) IQGAP1: insights into the function of a molecular puppeteer. Mol Immunol 65:336-49|
|Gerbec, Zachary J; Thakar, Monica S; Malarkannan, Subramaniam (2015) The Fyn-ADAP Axis: Cytotoxicity Versus Cytokine Production in Killer Cells. Front Immunol 6:472|
|Rajasekaran, Kamalakannan; Kumar, Pawan; Schuldt, Kristina M et al. (2013) Signaling by Fyn-ADAP via the Carma1-Bcl-10-MAP3K7 signalosome exclusively regulates inflammatory cytokine production in NK cells. Nat Immunol 14:1127-36|