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• W2024367381 abstract "Rho family members include RhoA, RhoB, and RhoC, Rac1 and Rac2, Cdc42Hs, RhoG, and TC10. These proteins function as binary switches by cycling between the active GTP-bound state and the inactive GDP-bound state. Three classes of regulatory proteins control the guanine nucleotide binding cycle of Rho family GTPase: guanine nucleotide exchange factors (GEFs) promote the transition from the inactive GDP-bound state to the active GTP-bound conformation; GTPase-activating proteins (GAPs) stimulate the inactivation; and guanine nucleotide dissociation inhibitors (GDIs) act to lock the GTPase in either the active or inactive state. Activated GTPases are consequently able to regulate diverse cellular processes by coupling to multiple biochemical effector signaling pathways. Immunological interest in Rho GTPases stems from genetic evidence demonstrating that Rho GTPases play a critical role in regulating cell survival, proliferation, and differentiation during lymphocyte development. Moreover, in biochemical studies, regulators of Rho GTPases have emerged as important components of signal transduction pathways used by antigen receptors, costimulatory, cytokine, and chemokine receptors to regulate the immune response. The present review will summarize data regarding the role of the Rho family GTPases Cdc42Hs, Rac1, and RhoA in cells of the immune system and will discuss current models for the signaling networks regulating the activity of these GTPases in lymphocytes. A plethora of GEFs (at least 15 have been identified), GAPs (comprising around 10 GAPs to date), and Rho GDIs can regulate the specific actions of Rho family GTPases in response to extracellular stimuli. Progress in understanding the upstream signaling pathways that control the function or cell localization of these regulatory proteins has highlighted their potential to link Rho GTPases to immune stimuli. The best characterized Rho family GEF in lymphocytes is Vav1, which is specific for Rac and is regulated by tyrosine phosphorylation. Vav1 is a 95 kDa protein with src homology (SH) 2 and SH3 domains and a Dbl homology region, which is a characteristic marker of GEFs for Rho family GTPases (for review,4Collins T.L Deckert M Altman A Views on Vav.Immunol. Today. 1997; 18: 221-225Abstract Full Text PDF PubMed Scopus (96) Google Scholar). Initial studies suggested that Vav functioned as a ras GEF, but this hypothesis has not been substantiated by extensive experimental studies; rather, Vav functions as a GEF for Rac. The guanine nucleotide exchange activity of Vav is regulated by tyrosine phosphorylation: in Cos cells Vav is tyrosine phosphorylated in response to coexpression of activated src family kinases, leading to an elevation in its catalytic activity as a rac GEF (5Crespo P Schuebel K.E Ostrom A.A Gutkind J.S Bustelo X.R Phosphotyrosine-dependent activation of Rac-1 GDP/GTP exchange by the vav proto-oncogene product.Nature. 1997; 385: 169-172Crossref PubMed Scopus (680) Google Scholar). Physiologically, Vav is rapidly and transiently tyrosine phosphorylated in response to antigen receptor ligation in T cells, B cells, and mast cells. There are also protein complexes formed between Vav and the tyrosine kinase ZAP-70 or Vav and the adapter molecule SH2 domain leukocyte protein of 76 kDa (SLP-76) in activated T cells (35Wange R.L Samelson L.E Complex complexes signaling at the TCR.Immunity. 1996; 5: 197-205Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar, 37Wu J Zhao Q Kurosaki T Weiss A The Vav binding site (Y315) in ZAP-70 is critical for antigen receptor-mediated signal transduction.J. Exp. Med. 1997; 185: 1877-1882Crossref PubMed Scopus (78) Google Scholar) that are probably important in regulating Vav cellular localization and catalytic activity. The critical regulatory sites for Vav tyrosine phosphorylation have not been identified, and it is not proven that antigen receptors induce tyrosine phosphorylation of Vav on the crucial sites that stimulate its catalytic activity. Nevertheless, a role for Vav in T cell antigen receptor (TCR) function is supported by the observation that mice deficient in Vav1 display defects in thymocyte positive selection (32Turner M Mee P.J Walters A.E Quinn M.E Mellor A.L Zamoyska R Tybulewicz V A requirement for the Rho-family GTP exchange factor Vav in positive and negative selection of thymocytes.Immunity. 1997; 7: 451-460Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar). Furthermore, experiments in cultured T cell lines show that overexpression of Vav dramatically potentiates TCR-mediated transcriptional activation of the nuclear factor of activated T cells (NFAT), particularly in synergy with the T cell adapter molecule SLP-76 (for review,35Wange R.L Samelson L.E Complex complexes signaling at the TCR.Immunity. 1996; 5: 197-205Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar). Signals generated by interactions between the costimulatory receptor CD28 and its physiological ligands B7-1/B7-2 are critical for T cell activation. One key to understanding the ability of CD28 to modulate TCR signal transduction is to identify substrates for CD28-regulated tyrosine kinases. Vav1 was originally identified as a substrate for antigen receptor-activated tyrosine kinases. Interestingly, however, engagement of CD28 with B7-1 or B7-2 can induce a rapid and sustained tyrosine phosphorylation of Vav in the absence of simultaneous ligation of the TCR (21Nunes J.A Collette Y Truneh A Olive D Cantrell D.A The role of p21ras in CD28 signal transduction triggering of CD28 with antibodies, but not the ligand B7-1 activates p21ras.J. Exp. Med. 1994; 180: 1067-1076Crossref PubMed Scopus (167) Google Scholar, 30Tuosto L Michel F Acuto O p95vav associates with tyrosine-phosphorylated SLP-76 in antigen-stimulated T cells.J. Exp. Med. 1996; 184: 1161-1166Crossref PubMed Scopus (173) Google Scholar). Vav is thus activated by the initial contact between T cells and antigen-presenting cells (APCs). Moreover, a unique protein complex consisting of tyrosine phosphorylated Vav and tyrosine phosphorylated SLP-76 assembles in TCR-triggered and CD28-costimulated T cells. Vav/SLP-76 complexes are thus integrating signals initiated by the TCR and CD28 and hence are good candidates to couple these receptors to Rac signaling pathways in T cells (Figure 1). A second clue that CD28 is linked to the regulatory networks that control the activity of Rho family GTPases has come from characterization of proteins that are tyrosine phosphorylated by CD28- but not TCR-activated tyrosine kinases. Thus, ligation of CD28 with B7-1 and B7-2 induces tyrosine phosphorylation of a 62 kDa adapter protein, now identified as p62dok (22Nunes J Truneh A Olive D Cantrell D.A Signal transduction by CD28 ligands B7-1 and B7-2 CD28 regulation of tyrosine kinase adapter molecules.J. Biol. Chem. 1996; 251: 1591-1598Google Scholar, 2Carpino N Wisniewski D Strife A Marshak D Kobayashi R Stillman B Clarkson B p62(dok) a constitutively tyrosine-phosphorylated, GAP-associated protein in chronic myelogenous leukemia progenitor cells.Cell. 1997; 88: 197-204Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar, 38Yamanashi Y Baltimore D Identification of the Abl- and rasGAP-associated 62 kDa protein as a docking protein, Dok.Cell. 1997; 88: 205-211Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar). This protein contains a pleckstrin homology (PH) domain and forms a protein complex with p120 ras GAP and p190 rho GAP (Figure 1). Current models for the involvement of p62dok in the regulation of Rho family GTPases are based on the assumption that tyrosine phosphorylation of p62dok will modulate the cellular distribution of associated ras GAPs and rho GAPs and sequester these negative regulators away from active Ras and Rac molecules, thereby prolonging the activation of Rac or Rho effector pathways. The ability of CD28 to regulate Vav tyrosine phosphorylation in combination with its link to p62dok illustrates that CD28 is uniquely coupled to the regulatory networks that control the activity of Rho family GTPases (Figure 1). Rho family GEFs characteristically consist of a catalytic Dbl homology domain flanked by a PH domain that is critical for GEF function (for review,3Cerione R Zheng Y The Dbl family of oncogenes.Curr. Opin. Cell Biol. 1996; 8: 216-222Crossref PubMed Scopus (466) Google Scholar). PH domains selectively bind polyphosphoinositides, and these interactions have the potential to modify GEF activity allosterically and induce relocalization of the protein to specific subcellular locations or defined areas of the plasma membrane (23Rameh L.E Arvidsson A.-K Carraway I K.L Couvillon A.D Rathbun G Crompton A VanRenterghem B Czech M.P Ravichandran K.S Burakoff S.J et al.A comparative analysis of the phosphoinositide binding specificity of pleckstrin homology domains.J. Biol. Chem. 1997; 272: 22059-22066Crossref PubMed Scopus (425) Google Scholar). For example, the amino-terminal PH domain of T lymphoma invasion and metastasis protein (TIAM-1), a GEF for Rac, shows selective binding for phosphatidylinositol 3,4,5-trisphosphate (PI[3,4,5]P3). PI(3,4,5)P3 is generated by activated phosphatidylinositol 3-kinase (PI3K), and TIAM-1 may therefore be recruited to the plasma membrane as a consequence (23Rameh L.E Arvidsson A.-K Carraway I K.L Couvillon A.D Rathbun G Crompton A VanRenterghem B Czech M.P Ravichandran K.S Burakoff S.J et al.A comparative analysis of the phosphoinositide binding specificity of pleckstrin homology domains.J. Biol. Chem. 1997; 272: 22059-22066Crossref PubMed Scopus (425) Google Scholar). Activation of PI3K resulting in elevated cellular levels of PI(3,4,5)P3 is a common response to the triggering of antigen receptors and costimulatory molecules, such as CD28 in T cells and CD19 in B cells; hematopoietic cytokines, such as interleukin-2 (IL-2), IL-4, and IL-7, also stimulate PI3K (36Ward S.G June C.H Olive D PI 3-kinase a pivotal pathway in T cell activation.Immunol. Today. 1996; 17: 187-198Abstract Full Text PDF PubMed Scopus (172) Google Scholar). In this context, experiments with constitutively active PI3K mutants have shown that the D-3 phosphoinositide products of PI3K are sufficient to induce Rac- and Rho-mediated cytokeletal responses in fibroblasts (24Reif K Nobes C.D Thomas G Hall A Cantrell D.A Phosphatidylinositol 3-kinase signals activate a selective subset of Rac/Rho-dependent effector pathways.Curr. Biol. 1996; 6: 1445-1455Abstract Full Text Full Text PDF PubMed Google Scholar). PI3K thus has the potential to couple immune receptors to Rac/Rho signaling pathways controling actin cytoskeleton rearrangements in lymphocytes. These responses will be important for lymphocyte motility, cell–cell contacts, and cell adhesion. Rac1, Cdc42Hs, and RhoA are important mediators of Ras-induced cell transformation and DNA synthesis (27Symons M Rho family GTPases the cytoskeleton and beyond.Trends Biochem. Sci. 1996; 21: 178-181Abstract Full Text PDF PubMed Scopus (260) Google Scholar). The GTPase Ras plays an essential role in lymphocytes: Ras function is important for thymocyte development and regulates the positive selection of thymocytes (26Swan K.A Albeerola-lla J Gross J.A Appleby M.W Forbush K.A Thomas J.F Perlmutter R.M Involvement of p21ras distinguishes positive and negative selection in thymocytes.EMBO J. 1995; 14: 276-285Crossref PubMed Scopus (272) Google Scholar). Ras also couples antigen receptors to the signaling pathways that regulate the activity of NFAT (10Genot E Cleverley S Henning S Cantrell D.A Multiple p21ras effector pathways regulate nuclear factor of activated T cells.EMBO. J. 1996; 15: 3923-3933Crossref PubMed Scopus (151) Google Scholar). Ras signals are thus critical for cytokine gene induction in peripheral lymphocytes; notably, defects in the activation of Ras signaling pathways have been linked to T cell anergy. For induction of cytokine genes in T cells and mast cells, it is apparent that the coordinated action of multiple Ras effector pathways is required (10Genot E Cleverley S Henning S Cantrell D.A Multiple p21ras effector pathways regulate nuclear factor of activated T cells.EMBO. J. 1996; 15: 3923-3933Crossref PubMed Scopus (151) Google Scholar, 31Turner H Cantrell D.A Distinct Ras effector pathways are involved in FcεR1 regulation of the transcriptional activity of Elk-1 and NFAT in mast cells.J. Exp. Med. 1997; 185: 43-57Crossref PubMed Scopus (62) Google Scholar). One well-established Ras effector is Raf1, which regulates MEK/ERK2 kinases. However, the actions of Ras in lymphocytes cannot be explained solely in terms of a Raf1/MEK/ERK2 pathway as a Ras effector system. Rather, a Ras effector pathway mediated by Rac1 has a critical role in the Ras signaling pathways that couple antigen receptors to NFAT in T cell and mast cells (10Genot E Cleverley S Henning S Cantrell D.A Multiple p21ras effector pathways regulate nuclear factor of activated T cells.EMBO. J. 1996; 15: 3923-3933Crossref PubMed Scopus (151) Google Scholar, 31Turner H Cantrell D.A Distinct Ras effector pathways are involved in FcεR1 regulation of the transcriptional activity of Elk-1 and NFAT in mast cells.J. Exp. Med. 1997; 185: 43-57Crossref PubMed Scopus (62) Google Scholar). Precedence for functional links between GTPases exist in Schizosaccharomyces pombe, where a direct interaction between Ras and Rho family GEFs has been observed: Ras1 binds directly to Scd1, a GEF for Cdc42. A similar hierachical cascade could occur in lymphocytes where activated Ras could bind and modulate the catalytic activity of a rac GEF. A second possible model could involve GAP proteins: p190 rho GAP functions biochemically as a GAP for Cdc42, Rac, and Rho and functions to terminate signals from these GTPases. In a variety of cells, including lymphocytes, a complex comprising p190 rho GAP and p120 ras GAP has been described (22Nunes J Truneh A Olive D Cantrell D.A Signal transduction by CD28 ligands B7-1 and B7-2 CD28 regulation of tyrosine kinase adapter molecules.J. Biol. Chem. 1996; 251: 1591-1598Google Scholar, 2Carpino N Wisniewski D Strife A Marshak D Kobayashi R Stillman B Clarkson B p62(dok) a constitutively tyrosine-phosphorylated, GAP-associated protein in chronic myelogenous leukemia progenitor cells.Cell. 1997; 88: 197-204Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar, 38Yamanashi Y Baltimore D Identification of the Abl- and rasGAP-associated 62 kDa protein as a docking protein, Dok.Cell. 1997; 88: 205-211Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar). Indeed, in cells lacking p120 ras GAP, tyrosine phosphorylation of p190 rho GAP in response to receptor triggering is reduced (34van der Geer P Henkemeyer M Jacks T Pawson T Aberrant Ras regulation and reduced p190 tyrosine phosphorylation in cells lacking p120-GAP.Mol. Cell Biol. 1997; 17: 1840-1847Crossref PubMed Scopus (67) Google Scholar). Interactions between activated Ras and p120 ras GAP could physically sequester p190 rho GAP, preventing its interaction with Rho family GTPases, thereby promoting their activation. There are several functional or genetic studies that support the biochemical data indicating that Rac plays a critical role in lymphocyte activation. First, defective cytokine gene expression in activated peripheral T cells is observed in mice deficient in Vav1, the Rac GEF, indicating a role for Rac in these critical antigen and costimulatory receptor responses (8Fischer K.-D Zmuidzinas A Gardner S Barbacid M Bernstein A Guidos C Defective T-cell receptor signaling and postive selection of Vav-deficient CD4+ CD8+ thymocytes.Nature. 1995; 374: 474-477Crossref PubMed Scopus (286) Google Scholar). There are also defects in thymocyte positive selection in Vav1−/− mice (32Turner M Mee P.J Walters A.E Quinn M.E Mellor A.L Zamoyska R Tybulewicz V A requirement for the Rho-family GTP exchange factor Vav in positive and negative selection of thymocytes.Immunity. 1997; 7: 451-460Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar). Second, in vitro experiments with activated and inhibitory Rac mutants in T cell and mast cell lines show unequivocally that Rac function is essential for transcriptional activation of NFAT, providing one good explanation for the Rac signaling requirement in cytokine gene induction (10Genot E Cleverley S Henning S Cantrell D.A Multiple p21ras effector pathways regulate nuclear factor of activated T cells.EMBO. J. 1996; 15: 3923-3933Crossref PubMed Scopus (151) Google Scholar, 31Turner H Cantrell D.A Distinct Ras effector pathways are involved in FcεR1 regulation of the transcriptional activity of Elk-1 and NFAT in mast cells.J. Exp. Med. 1997; 185: 43-57Crossref PubMed Scopus (62) Google Scholar). There is no direct biochemical information about Rho activation (GTP occupancy of Rho) in lymphocytes. Nevertheless, there is compelling genetic data showing that Rho function is important in lymphocyte biology. Most advances in understanding the cellular function of Rho are based on the targeted expression of Clostridium botulinum C3-exoenzyme. This enzyme specifically ADP-ribosylates Rho molecules, preventing their interactions with downstream effectors molecules: its use has implicated RhoA in integrin-mediated adhesion (15Laudanna C Campbell J.J Butcher E.C Role of Rho in chemoattractant-activated leukocyte adhesion through integrins.Science. 1996; 271: 981-983Crossref PubMed Scopus (433) Google Scholar) and lymphocyte-mediated cytotoxicity (14Lang P Bertoglio J Inhibition of lymphocyte-mediated cytotoxicity by Clostridium botulinum C3 transferase.Meth. Enzymol. 1995; 256: 320-327Crossref PubMed Scopus (5) Google Scholar). Inactivation of Rho function in the thymus has also been achieved by thymic targeting of a transgene encoding C. botulinum C3-transferase, allowing assessment of the function of Rho in normal T cell biology (11Henning S Galandrini R Hall A Cantrell D.A The GTPase Rho has a critical regulatory role in thymocyte development.EMBO. J. 1997; 16: 2397-2407Crossref PubMed Scopus (125) Google Scholar) (Figure 2). Thymocytes that lack Rho function show selective proliferative defects during T cell development that severely impair the generation of normal numbers of thymocytes and mature peripheral T cells (9Gallandrini R Henning S Cantrell D.A Different functions for the GTPase Rho in prothymocytes and late pre-T cells.Immunity. 1997; 7: 163-174Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). Notably, in CD44+/CD25+ pro–T cells and CD44−/CD25+ early pre–T cells, Rho regulates cell survival (Figure 2). The survival of these cells is normally controlled by IL-7 (1Akashi K Kondo M von Freeden-Jeffry U Murray R Weissman I.L Bcl-2 rescues T lymphopoiesis in interleukin-7 receptor-deficient mice.Cell. 1997; 89: 1033-1041Abstract Full Text Full Text PDF PubMed Scopus (526) Google Scholar, 17Maraskovsky E O'Reilly L.A Teepe M Corcoran L.M Peschon J.J Strasser A Bcl-2 can rescue T lymphocyte development in interleukin-7 receptor-deficient mice but not in mutant rag-1-/- mice.Cell. 1997; 89: 1011-1019Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar). The thymic phenotype caused by loss of Rho function resembles the one caused by a loss in components of the IL-7 receptor signaling complex, suggesting that Rho is a component of the signaling pathways used by IL-7 to control cell survival. It is proposed that IL-7 regulates survival signaling pathways in thymocytes by controlling cellular levels of Bcl-2. The cellular deficit in Rho− thymi can be rescued by expression of the survival protein Bcl-2; it is therefore tempting to speculate that Rho acts as an intracellular link between the IL-7 receptor and the events that control expression or function of Bcl-2 family proteins. For Cdc42, like Rho, there is little direct biochemical data indicating its role in lymphocytes. However, genetic analyses indicate its importance for lymphocyte function. The coordinated regulation of the actin cytokeleton is important for cell motility and for T cell interactions with epthelial cells and APCs and thus for T cell activation. Studies using activated and inhibitory mutants of Cdc42Hs (V12Cdc42Hs and N17Cdc42Hs, respectively), have provided strong evidence linking Cdc42Hs to the regulation of the cytoskeleton in hematopoietic cells: Cdc42Hs can control TCR-induced cytoskeletal changes in cell polarization. In particular, Cdc42Hs function is essential for regulating T cell polarization toward APCs (25Stowers L Yelon D Berg L.J Chant J Regulation of the polarization of T cells toward antigen-presenting cells by Ras-related GTPase CDC42.Proc. Natl. Acad. Sci. USA. 1995; 92: 5027-5031Crossref PubMed Scopus (344) Google Scholar), a process that is critical for efficient T cell–APC contact and the directed release of cytokines. This concept has been consolidated by observations that the genetic defect in Wiscott-Aldrich immunodeficiency syndrome (WAS) patients maps to an effector protein for Cdc42Hs, termed WASp (12Kirchhausen T Rosen F.S Disease mechanism unravelling Wiskott-Aldrich syndrome.Curr. Biol. 1996; 6: 676-678Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). Overexpression of WASp leads to clustering of actin. It is possible that WASp binds actin directly or indirectly through its carboxy-terminal domain resulting in the accumulation of actin at certain sites in the cell, this process being initially triggered by the activation of Cdc42Hs. The defects in WAS patients include cytoskeletal and cell activation abnormalities in lymphocytes. WASp-deficient cells have a paucity in microvilli on the cell surface and poor response to protein antigens, possibly due to defective T cell–APC interactions. In the past couple of years a burgeoning number of effectors for Rho family GTPases have been identified in yeast two-hybrid screens, genetic analyses, or affinity column purifications (for reviews,28Tapon N Hall A Rho, Rac and Cdc42 GTPases regulate the organization of the actin cytoskeleton.Curr. Opin. Cell Biol. 1997; 9: 86-92Crossref PubMed Scopus (696) Google Scholar, 33Van Aelst L D'Souza-Schorey C Rho GTPases signaling networks.Genes and Dev. 1997; 11: 2295-2322Crossref PubMed Scopus (2096) Google Scholar). The minimal consensus Cdc42/Rac-binding motif stretches over 18 amino acids and is referred to as CRIB motif (Cdc42/Rac interactive binding). CRIB motif–containing proteins include the serine/threonine kinase family of p21-associated kinases (PAK) and mixed-lineage kinase 2,3 (MLK-2,3), the tyrosine kinase p120Ack, and WASp. However, there are also proteins that associate with Cdc42/Rac but lack a CRIB motif. Examples are POR1 (partner of Rac1), p67phox (component of the NADPH oxidase complex found in phagocytic cells), MEK kinase (MEKK)-1,4, or phosphatidylinositol 4-phosphate 5-kinase (PI4P 5-kinase). As yet, no consensus Rho binding motif has been identified. Putative effectors for Rho include three serine/threonine kinases, protein kinase C–related kinase 1,2 (PRK1 and PRK2) and Rho-associated coiled coil–containing protein kinase (p160ROCK), structural proteins like rhophilin and proteins with unknown function such as rhotekin and citron, and the recently described mammalian homolog of the Drosophila melanogaster diaphanous protein, p140 mDia (for review,19Narumiya S Ishizaki T Watanabe N Rho effectors and reorganisation of the actin cytoskelton.FEBS Lett. 1997; 410: 68-72Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar). Analysis of the immunological role of these Rho family effectors is at an early stage. As discussed, genetic defects in WAS map to WASp, an effector protein for Cdc42Hs. There is also immunological interest in the PAK family of serine/threonine kinases, which can interact with activated Rac GTPases. This interest stems from observations that the Nef protein, which is essential for efficient viral replication of HIV retroviruses, specifically associates with PAK-like p62 and p72 serine/threonine kinases (for review,6Cullen B HIV1 is Nef a PAK animal?.Curr. Biol. 1996; 6: 1557-1559Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). Cdc42 and Rac are thus implicated in the regulation of HIV replication (16Lu X Wu X Plemenitas A Yu H Sawai E.T Abo A Peterlin B.M CDC42 and Rac1 are implicated in the activation of the Nef-associated kinase and replication of HIV-1.Curr. Biol. 1996; 6: 1677-1684Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). Defining the signaling networks centered around the PAKs is therefore an important area of investigation relevant to the biology of HIV infections. Examples of additional Rac/Rho effector pathways with potentially significant roles in lymphocytes are highlighted below. The first biological function for Rho GTPases established in fibroblasts was the dynamic organization of the actin cytoskeleton and the assembly of associated integrin structures. Cdc42, Rac1, and RhoA are responsible for distinct patterns of actin reorganization. RhoA regulates the formation of actin stress fibers and focal adhesions, and Rac1 controls lamellipodia formation and focal complex assembly and subsequently can activate Rho-mediated cytoskeletal changes. Cdc42Hs first triggers induction of microspikes and filopodia but consecutively can induce Rac- and Rho-mediated responses (20Nobes C Hall A Rho, Rac and Cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibres, lamellipodia and filopodia.Cell. 1995; 81: 53-62Abstract Full Text PDF PubMed Scopus (3728) Google Scholar). Current models thus allow Cdc42Hs, Rac, and Rho to have unique functions in control of the actin cytokeleton but importantly link these GTPases in a linear cascade in which Cdc42Hs stimulate Rac1 responses, which in turn initiate RhoA responses in controlling the organization of the actin cytoskeleton (20Nobes C Hall A Rho, Rac and Cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibres, lamellipodia and filopodia.Cell. 1995; 81: 53-62Abstract Full Text PDF PubMed Scopus (3728) Google Scholar). As discussed, there is good genetic evidence for Cdc42 regulation of the actin cytoskeleton in lymphocytes; fibroblast models would therefore predict that Cdc42Hs would initiate Rac- and Rho-controlled cytoskeletal changes in lymphocytes. In this context, a link between Rac and the maintenance of the actin cytoskeleton, and cell attachment in lymhocyte biology is suggested by studies of TIAM-1. TIAM-1 is a GEF with selectivity for Rac and was identified as an invasion and metastasis-inducing gene in T lymphoma cells (18Michiels F Habets G Stam J van der Kammen R Collard J A role for Rac in Tiam1-induced membrane ruffling and invasion.Nature. 1995; 375: 338-340Crossref PubMed Scopus (508) Google Scholar). This highlights the potential of Rac to be a critical regulator of lymphocyte motility. Nevertheless, studies on TIAM-1 regulation of the actin cytoskeleton have been performed exclusively in fibroblasts, and a general model for Rac and Rho control of the actin cytoskeleton in lymphocytes has not yet been established. This is a neglected but important facet of lymphocyte signal transduction, but it must also be emphasized that Rho GTPases control a variety of cell responses, including regulation of gene transcription and cell cycle progression. The role of Rho GTPases during these responses is likely to be distinct to the one in maintaining the actin cytoskeleton. In this context, it is essential to note that multiple effectors exist for activated Cdc42, Rac, and Rho. Some of the effectors regulate the actin cytoskelton, but others have quite different functions. Potential effectors important for lymphocyte biology are introduced below. Rac is important for cytokine gene regulation in lymphocytes. One distal effector pathway that could explain the role of Rac during this process involves the mitogen-activated protein (MAP) kinases JNK/p38, which are activated by cytokines; the FcεR1 in mast cells; the B cell antigen receptor in B cells; and by the combined triggering of TCR and CD28 in T cells. Substrates for these MAP kinases include transcription factors such as ATF-2, c-Jun, and Ets family proteins. There is evidence for functional coupling between Rac and the JNK pathway in lymphocytes: expression of active mutants of Rac can induce the JNK/p38 pathway in T cells. Moreover, FcεR1 activation of JNK in Cos cells, a heterologous model cell system, is dependent on Rac (29Teramoto H Salem P Robbins K.C Bustelo X.R Gutkind J.S Tyrosine phosphorylation of the vav proto-oncogene product links FcεRI to the Rac1-JNK pathway.J. Biol. Chem. 1997; 272: 10751-10755Crossref PubMed Scopus (105) Google Scholar). These studies have generated a model that links antigen receptors to Rac, then to JNK, and finally to transcription factors involved in cytokine gene induction. The details of this model need to be resolved before it can be validated. At present, MEKK-1,4 are the strongest candidates to couple Rac to the JNK/p38 MAP kinases (7Fanger G.R Lassignal Johnson N Johnson G.L MEK kinases are regulated by EGF and selectively interact with Rac/Cdc42.EMBO J. 1997; 16: 4961-4972Crossref PubMed Scopus (254) Google Scholar). There are also two provisos about this model: first, it is not meant to imply that activation of MAP kinases is the sole function for Rac in cytokine gene induction; second, there are Rac-independent pathways for activation of JNK/p38 (7Fanger G.R Lassignal Johnson N Johnson G.L MEK kinases are regulated by EGF and selectively interact with Rac/Cdc42.EMBO J. 1997; 16: 4961-4972Crossref PubMed Scopus (254) Google Scholar). It remains thus a formal possibility that Rac and the JNK/p38 function in parallel to regulate cytokine gene expression. One other target for the action of both Rac and Rho that would have major impact on lymphocyte biology is PI4P 5-kinase (28Tapon N Hall A Rho, Rac and Cdc42 GTPases regulate the organization of the actin cytoskeleton.Curr. Opin. Cell Biol. 1997; 9: 86-92Crossref PubMed Scopus (696) Google Scholar). Evidence in nonlymphoid cells indicates that Rac1 and RhoA can regulate inositol lipid metabolism via a mechanism mediated by PI4P 5-kinase. This allows Rac1 and RhoA signals to regulate cellular levels of D-5 phosphoinositides, particularly phosphatidylinositol 4,5-bisphosphate (PI[4,5]P2). This lipid is a crucial molecule in antigen receptor signaling pathways in lymphocytes. First, its hydrolysis by the action of phospholipase C members generates inositol 1,4,5-trisphosphate and diacyglycerols that regulate intracellular calcium and protein kinase C, respectively. Second, the phosphorylation of PI(4,5)P2 by PI 3-kinase generates PI(3,4,5)P3, which in turn can be dephosphorylated to produce phosphatidylinositol 3,4-bisphosphate. These phosphoinositides and their products are important modifiers of intracellular signal transduction pathways at multiple stages of lymphocyte activation and growth. It will be important to define whether there is direct coupling between Rac and Rho and lipid kinases in lymphocytes. A fundamental feature of the biology of Rho GTPases is that receptors do not uniformly activate all cellular pathways mediated by a certain GTPase. Moreover, different GTPase effectors can function independently. The evidence that different Rac effector responses can be independently initiated stems from studies using Rac proteins with point mutations in their effector-binding regions, which results in selective loss of function (13Lamarche N Tapon N Stowers L Burbelo P.D Aspenstrom P Bridges T Chant J Hall A Rac and Cdc42 induce actin polymerization and G1 cell-cycle progression independently of p65(Pak) and the JNK/Sapk Map kinase cascade.Cell. 1996; 87: 519-529Abstract Full Text Full Text PDF PubMed Scopus (526) Google Scholar). In particular, two Rac mutants, RacL61A37 and RacL61C40, exclusively interact with different effector molecules. RacL61A37 is able to initiate JNK activation but does not induce cytoskeletal rearrangements. Conversely, RacL61C40 does not activate JNK but can stimulate actin polymerization and the generation of lamellipodia. Moreover, RacL61C40, but not RacL61A37, can initiate cell cycle progression in NIH3T3 cells. Similar mutational analysis of Cdc42 has also confirmed the existence of signaling pathways that independently signal to the JNK MAP kinase cascade and the cortical actin cytoskeleton. Rac effector pathways can not only function independently when triggered artificially with Rac effector mutants but can be independently activated by physiological stimuli that trigger endogenous Rho family GTPases (Figure 3). For example, PI3K effectively induces Rac-mediated changes in the actin cytoskeleton, such as formation of lamellipodia and focal adhesions (24Reif K Nobes C.D Thomas G Hall A Cantrell D.A Phosphatidylinositol 3-kinase signals activate a selective subset of Rac/Rho-dependent effector pathways.Curr. Biol. 1996; 6: 1445-1455Abstract Full Text Full Text PDF PubMed Google Scholar). However, PI3K signals are unable to induce Rac signaling pathways that regulate JNK activation. PI3K thus induces a selective subset of Rac-/Rho-mediated cellular responses that control the cortical actin cytoskeleton but is not sufficient to stimulate the full range of Rac- or Rho-coordinated pathways that couple to nuclear responses of transcription factor activation. Similarly, PI3K can induce Rho-mediated formation of actin stress fibers and focal complexes but not the Rho-regulated pathways that impinge on serum response factor transcriptional activation (24Reif K Nobes C.D Thomas G Hall A Cantrell D.A Phosphatidylinositol 3-kinase signals activate a selective subset of Rac/Rho-dependent effector pathways.Curr. Biol. 1996; 6: 1445-1455Abstract Full Text Full Text PDF PubMed Google Scholar). To explain these phenomena, it is necessary to evoke discrete subpopulations of Rho family GTPases that are linked to different upstream regulatory proteins and diverse effector pathways. The failure of PI3K-activated Rac or Rho to interact with the full range of Rac/Rho effector molecules shows that there must be subcellular compartmentalization of discrete pools of these proteins. A key to these processes will be some architectural organization of Cdc42, Rac, and Rho effector molecules by multivalent adapter, anchoring, or scaffold proteins. We now know that Rho GTPases are important for the regulation of different cellular responses essential for immune function, including regulation of cell survival, cell cycle progression, adhesion, and cytokine gene expression. However, our understanding of the exact makeup and biological function of the effector pathways that mediate these cellular responses of Rho GTPases in lymphocytes remains fragmentary. Studies of RhoA function in thymocyte development have indicated that there are not universal outcomes of activating Rho family GTPases but rather unique responses in different cell populations. This notion is likely to be a common theme, and it is conceivable that the pleotropic functions of Rho GTPases can be explained by the diversity of their different effectors. The outcome of Rho family GTPase activation by various immune stimuli will be determined by the unique expression patterns of different effector molecules in distinct cell types. A future challenge will be to characterize the expression patterns of effectors for Rho GTPases in lymphocytes; these studies will be the key to understanding the mechanisms for the generation of signaling heterogeneity in different lymphocyte subpopulations." @default.
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• W2024367381 title "Networking Rho Family GTPases in Lymphocytes" @default.
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