PIX is a Rho GTPase guanine nucleotide exchange aspect domain-containing signaling protein that associates with other proteins involved in cytoskeletal-membrane complexes. antigen receptor signaling was largely unaffected, with the exception of reduced phosphorylation of PAK and expression of GIT2 in both T cells and B cells. These results reveal specific functions for PIX in the immune system and suggest that redundancy with PIX precludes a more severe immune phenotype. The activation of lymphocytes by antigen is critical to the generation of specific immune responses. An antigen stimulates signaling cascades in T and B cells via the T-cell antigen receptor (TCR) and the B-cell antigen receptor (BCR). These signaling cascades produce multiple measurable outputs, including tyrosine phosphorylation of proteins, mitogen-activated protein kinase activation, calcium fluxing, and protein degradation. On a larger level, activation of signaling causes remodeling of macromolecular complexes, such as immune synapses or focal adhesions, enabling a cell to differentiate or to migrate (6, 46). One family of proteins that is important for organizing such signaling complexes in immune AMG706 cells is the Rho AMG706 GTPase guanine nucleotide exchange factors (RhoGEFs) (21, 55). RhoGEFs are associated with cytoskeletal remodeling, since they are enzymes that activate Rho family GTPases, such as Rho, Rac, or Cdc42, by catalyzing the exchange of GTP for GDP around the GTPase (26). RhoGEFs contain multiple protein conversation domains and bind to a variety of signaling proteins. The PIX (homology (DH) domain name, and a pleckstrin homology (PH) domain name for activation of Rho GTPases (also known as a RhoGEF domain name), but they differ in the lengths of their N- and C-terminal regions (15, 30): PIX contains an N-terminal calponin homology (CH) domain name (51), while PIX does not. Also, the PIX gene, but not the PIX gene, maps to the X chromosome (32). Both PIX proteins share a coiled-coiled domain name implicated in dimerization and a domain name called the GIT-binding sequence (50). Although PIX GEFs can activate Rac1 and Cdc42 GTPases, they are subject to many levels of control, including AMG706 requirements for phosphorylation (54), for monomerization or dimerization (16), for relief from an inhibitory domain name (15), and for binding to activated GTPases (3). PIX proteins associate with a wide variety of proteins, from your neuronal synapse protein Shank (41) and the polarity complex protein Scribble (1), to signaling proteins such as PAK or phosphatidylinositol 3-kinase (p85 subunit) (34, 60), to actin-associated proteins such as -parvin/affixin (49) and Abi-1 (12). PIX protein bind to degradation-related protein also, such as for example E3 AMG706 ubiquitin ligases c-Cbl (18) and atrophin-interacting proteins 4 (28), and calpain regulatory subunit (48). PIX protein may play jobs in lymphocyte disease by facilitating individual immunodeficiency pathogen Nef features (9) and through binding to X-linked lymphoproliferative disease proteins SAP (23). The predominant binding companions for PIX proteins, nevertheless, are GIT proteins (G-protein-coupled receptor kinase-interacting proteins 1 and 2), also called CAT proteins/p95PKL/APP1/2 (25). PIX protein and GIT proteins associate in large, stable oligomeric complexes that recruit Rac1 and Cdc42 GTPases and PAK kinases (45). These associations enable PIX protein participation in actin-dependent cell functions, such as migration (57), cell distributing (48), neurite extension (53, 61), and focal complexes (50). It is likely that these functions are tightly coordinated with those of GIT proteins, which include membrane recycling and endosomal dynamics (25). The mutation of HNRNPA1L2 PIX in mice results in neutrophils defective in orienting and migrating toward a chemoattractant (33). This phenotype resembles that of GIT2 knockout mice, which also have neutrophils with direction-sensing defects (36). In humans, PIX mutations are associated with X-linked mental retardation (32). PIX knockout lymphocytes have not been described in detail; however, results of studies on PIX in Jurkat T cells point to multiple functions for.