SOCS Pathway
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SOCS Pathway

SOCS (Suppressor of Cytokine Signaling) proteins attenuate Cytokine and Tyrosine Kinase receptor signaling pathways (including those that regulate the immune system) by providing a negative feedback signal to prevent excessive cellular activation that can be lethal. The SOCS proteins regulate signal transduction by combining direct inhibitory interactions with Cytokines and/or TYK receptors and signaling proteins such as the JAKs (Janus Kinases), STATs (Signal Transducer And Activator of Transcription) or IRS (Insulin Receptor Substrates) family members, with a generic mechanism of targeting associated proteins for degradation by the Proteasome (Ref.1).

The SOCS family (also termed as: SSI [STAT-induced STAT Inhibitors]/CIS [Cytokine Inducible SH2 containing protein]) contains eight members, SOCS1 through SOCS7 and CIS, each of which contains a central SH2 (Src Homology-2) domain, an amino-terminal domain of divergent sequence and a COOH-terminal conserved SOCS Box. At least four SOCS members (CIS and SOCS1, SOCS2, and SOCS3) are expressed in mammalian cells (Ref.2) that participate in the classical negative feedback loop. SOCS1 and SOCS3 inhibit cytokine signaling by binding directly to activated JAKs through their SH2 domains and inhibit JAK catalytic activity in a tissue-specific manner. CIS appears to compete with members of the STAT family of transcription factors for phosphotyrosine binding sites on activated Cytokine Receptors whereas the exact mechanism of action of SOCS2 is yet to be elucidated. CIS, SOCS1, SOCS2, and SOCS3 are generally present in cells at low levels, but their transcription is rapidly upregulated in response to stimulation by a wide range of cytokines, Growth Factors, and hormones. When overexpressed in cell lines, the SOCS proteins potently inhibit signaling by a large variety of stimuli (Ref.3).

Regulation of the JAK-STAT signaling by cytokines (Interferons; IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, IL-15 (Interleukins); hormones: Erythropoietin, Growth Hormones, Prolactin; and Growth Factors: EGF, PDGF, GCSF) is a critical point in the modulation of a wide spectrum of physiological settings including: cell proliferation, differentiation, development, immunity, apoptosis and hematopoiesis, that is achieved by SOCS proteins. The mechanisms by which SOCS proteins interfere with this pathway include direct inhibition of the catalytic activity of JAK kinases and competition between SOCS and STAT1/3 proteins for the same binding sites on activated receptors. SOCS proteins could also act as adapter proteins linking protein substrates to the ubiquitin machinery through the interaction of SOCS with ubiquitin ligase complexes (Ref.1). Following binding to their receptors, the cytokines and hormones activate the JAK family of kinases (JAK1, JAK2, JAK3 and Tyk2) that in turn phosphorylate the receptor associated STAT1/3 family of transcription factors, which causes them to form homo- or heterodimers. Phosphorylated STAT dimers translocate to the nucleus and regulate transcription of specific genes including those of CIS, SOCS1, SOCS2 and SOCS3 that in turn encode cytoplasmic proteins. The SOCS proteins thus generated recognize activated signaling molecules including the JAKs and STATs through their SH2 and N-terminal domains and thus act as autofeedback inhibitors (Ref.4). SOCS proteins (SOCS1 and SOCS3) also modulate Insulin signaling by the Insulin and IGF1 (Insulin-like Growth Factor-1) receptors by targeting the insulin receptor substrate proteins IRS1 and IRS2, two key signaling proteins in Insulin action, for ubiquitination and degradation by the ubiquitin-mediated proteasomal degradation (Ref.3).

The hallmark of the SOCS family is the SOCS Box, which mediates interaction with the Elongin-B/C complex and couples the SOCS and associated target proteins (JAKs and IRSs) to the proteasomal protein degradation pathway (Ref.4). The NH2-terminus of the SOCS Box contains a conserved Elongin-B/C binding motif (BC Box) that binds to Elongin-C, which in turn associates with a complex consisting of Elongin-B, a Cullin family member, and the RING finger protein Rbx-1 to form a multiprotein complex capable of acting as an E3 Ubiquitin Ligase. Together with an ATP-dependent ubiquitin-activating enzyme (E1) and an ubiquitin-conjugating enzyme (E2), the E3 Ubiquitin Ligase acts to tag proximal proteins with polyubiquitin chains. Polyubiquitination targets proteins for degradation by the Proteasome. Ubiquitin is then recycled by dUB (deubiquitinating enzymes) and the cycle continues. (Ref.5). Thus, targeting of SOCS proteins and their bound activated signaling molecules to the protein degradation pathway explains the fact that SOCS proteins simultaneously terminate a cytokines stimulation cycle and their own inhibitory action so that cells may respond to a second round of stimulation (Ref.4).

The SOCS proteins play a central role in controlling the intensity and/or duration of a cells response to a diverse range of extracellular stimuli by suppressing the signal transduction processes and for that reason, they are now speculated as potent therapeutic agents for treatment of a wide range of malignancies arising as a result of uncontrolled activation of signaling pathways. The role of SOCS as key physiological regulators of cytokines responses that also regulate the inflammatory systems has been exploited for treating inflammatory diseases by modulating extracellular and intracellular signaling pathways (Ref.6). Several studies have shown the SOCS family members to be therapeutically useful for treatment of certain hematologic malignancies induced by tyrosine kinase fusions. In addition, they may be useful in novel or adjunctive treatment strategies for inhibition of the JAK-STAT pathway in hematologic malignancies known to involve constitutive activation of the pathway, including acute myeloid leukemia, chronic lymphocytic leukemia and for treatment of Hepatitis C virus infection and other infectious diseases (Ref.7). Till date, although the role of SOCS proteins in tumor suppression and their therapeutic manipulation in infectious diseases is largely an unexplored territory, further analysis of SOCS action in innate and adaptive immune responses might yield valuable insights (Ref.1).