Kinase inhibition, competitive binding and proteasomal degradation: resolving the molecular function of the suppressor of cytokine signaling (SOCS) proteins

The suppressor of cytokine signaling (SOCS) family of proteins are key negative regulators of cytokine and growth factor signaling. They act at the receptor complex to modulate the intracellular signaling cascade, preventing excessive signaling and restoring homeostasis. This regulation is critical to the normal cessation of signaling, highlighted by the complex inflammatory phenotypes exhibited by mice deficient in SOCS1 or SOCS3. These two SOCS proteins remain the best characterized of the eight family members (CIS, SOCS1-7), and in particular, we now possess a sound understanding of the mechanism of action for SOCS3. Here, we review the mechanistic role of the SOCS proteins and identify examples where clear, definitive data have been generated and discuss areas where the information is less clear. From this functional viewpoint, we discuss how the SOCS proteins achieve exquisite and specific regulation of cytokine signaling and highlight outstanding questions regarding the function of the less well-studied SOCS family members.