Controlling cytokine signaling by constitutive inhibitors Kriti Rakesh a , Devendra K. Agrawal a,b,c, * a Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE 68178, USA b Department of Internal Medicine, Creighton University School of Medicine, Omaha, NE 68178, USA c Department of Medical Microbiology and Immunology, CRISS I Room 131, 2500 California Plaza, Creighton University School of Medicine, Omaha, NE 68178, USA Received 11 January 2005; accepted 14 April 2005 Abstract Cytokines are secreted proteins that regulate diverse biological functions by binding to receptors at the cell surface to activate complex signal transduction pathways including the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Stringent mechanisms of signal attenuation are essential for ensuring an appropriate, controlled cellular response. Three families of proteins, the SH2-containing phosphatases (SHP), the protein inhibitors of activated STATs (PIAS), and the suppressors of cytokine signaling (SOCS), inhibit specific and distinct aspects of cytokine signal transduction. The analysis of mice lacking genes for members of the SHP has shed much light on the roles of these proteins in vivo. In recent in vitro studies, the protein modifiers ubiquitin and small ubiquitin-like modifier (SUMO) have emerged as key players in the strategies employed by SOCS and PIAS to repress signaling. This review throws light on the mechanisms of action of these regulators as being evolved by the latest researches. # 2005 Elsevier Inc. All rights reserved. Keywords: Cytokines; JAK/STAT signalling; SOCS; SHP; PIAS; Inhibitors of signaling 1. Introduction Cytokines are secreted glycoproteins which play a pivo- tal role in the development and pathology of human disease, including diseases of the immune system. Since their discovery and cloning, it has become abundantly clear that cytokines play critical roles in regulating immune and inflammatory cells. For instance, the development of lym- phoid and myeloid cells is now known to be controlled to a major degree by cytokines such as interleukin IL-7, IL-3, granulocyte-monocyte colony-stimulating factor (GM- CSF), and granulocyte colony-stimulating factor, among others. Similarly, numerous studies have documented the role of IL-6 in promoting inflammatory responses. Other cytokines can be classified as immunoregulatory cyto- kines. For example, IL-2 controls lymphoid homeostasis both positively and negatively; in addition, the differentia- tion of CD4 + T-helper (Th) cells into Th1 and Th2 subsets has been documented to be controlled in large measure by cytokines. For instance, IL-12 promotes the differentiation of naı ¨ve Th cells to those that produce interferon (IFN)-g and lymphotoxin (Th1 cells), whereas IL-4 drives the differentiation of T cells to those that secrete IL-4, IL-5, and IL-10 (Th2 cells). Signaling receptors are members of two structurally related families, termed type I and type II cytokine receptors. Type I cytokine receptors include those for cytokines such as erythropoietin, prolactin, growth hormone (GH), thrombopoietin, granulocyte colony-sti- mulating factor, and GM-CSF. In addition, many, but not all of the receptors for different interleukins are part of this family: IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL- 11, IL-12, IL-13, and IL-15. The type II cytokine receptors include those for the IFNs (IFN-a, IFN-b, and IFN-g) and IL-10. Of note, the receptors for IL-1, IL-18, IL-8, trans- forming growth factor-b, and tumor necrosis factor are not part of this family. Type I and II cytokine receptors lack intrinsic kinase activity and instead rely on Janus kinase (Jak) proteins to initiate signaling. Once a cytokine binds to its corresponding receptor, it leads to conformational changes in the receptor initiating activation of JAK. JAKs, a family of four non-receptor tyrosine kinases, selectively phosphorylate STATs, leading to their activation, dissocia- tion from JAK, dimerization and translocation to the nucleus (Fig. 1). This pathway is crucial to many responses like hematopoiesis, immune regulation and oncogenesis. www.elsevier.com/locate/biochempharm Biochemical Pharmacology 70 (2005) 649–657 * Corresponding author. Tel.: +1 402 280 2938; fax: +1 402 280 1421. E-mail address: dkagr@creighton.edu (D.K. Agrawal). 0006-2952/$ – see front matter # 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.bcp.2005.04.042