Signal Transduction Pathways in Chronic Inflammatory Autoimmune Disease: Small GTPases



Kris A Reedquist*, Paul P Tak
Division of Clinical Immunology and Rheumatology, Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, The Netherlands


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© Reedquist and Tak Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to this author at the Division of Clinical Immunology and Rheumatology, Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, The Netherlands; Tel: +31 20 566 6913; Fax: +31 20 691 9658; E-mail: k.a.reedquist@amc.uva.nl


Abstract

Ras superfamily small GTPases represent a wide and diverse class of intracellular signaling proteins that are highly conserved during evolution. These enzymes serve as key checkpoints in coupling antigen receptor, growth factor, cytokine and chemokine stimulation to cellular responses. Once activated, via their ability to regulate multiple downstream signaling pathways, small GTPases amplify and diversify signaling cascades which regulate cellular proliferation, survival, cytokine expression, trafficking and retention. Small GTPases, particularly members of the Ras, Rap, and Rho family, critically coordinate the function and interplay of immune and stromal cells during inflammatory respones, and increasing evidence indicates that alterations in small GTPase signaling contribute to the pathological behavior of these cell populations in human chronic inflammatory diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Here, we review how Ras, Rap, and Rho family GTPases contribute to the biology of cell populations relevant to human chronic inflammatory disease, highlight recent advances in understanding how alterations in these pathways contribute to pathology in RA and SLE, and discuss new therapeutic strategies that may allow specific targeting of small GTPases in the clinic.

Keywords: GTPases, systemic lupus erythematosus, matrix metalloproteinases, farnesyltransferase inhibitors..