SOCS proteins in regulation of receptor tyrosine kinase signaling.
Receptor tyrosine kinases (RTKs) are a family of cell surface receptors that play critical roles in signal transduction from extracellular stimuli. Many in this family of kinases are overexpressed or mutated in human malignancies and thus became an attractive drug target for cancer treatment. The signaling mediated by RTKs must be tightly regulated by interacting proteins including protein-tyrosine phosphatases and ubiquitin ligases. The suppressors of cytokine signaling (SOCS) family proteins are well-known negative regulators of cytokine receptors signaling consisting of eight structurally similar proteins, SOCS1-7, and cytokine-inducible SH2-containing protein (CIS). A key feature of this family of proteins is the presence of an SH2 domain and a SOCS box. Recent studies suggest that SOCS proteins also play a role in RTK signaling. Activation of RTK results in transcriptional activation of SOCS-encoding genes. These proteins associate with RTKs through their SH2 domains and subsequently recruit the E3 ubiquitin machinery through the SOCS box, and thereby limit receptor stability by inducing ubiquitination. In a similar fashion, SOCS proteins negatively regulate mitogenic signaling by RTKs. It is also evident that RTKs can sometimes bypass SOCS regulation and SOCS proteins can even potentiate RTKs-mediated mitogenic signaling. Thus, apart from negative regulation of receptor signaling, SOCS proteins may also influence signaling in other ways.
Division of Translational Cancer Research, Lund University, Medicon Village, Lund, Sweden.
Julhash U
JU
Kazi
Nuzhat N
NN
Kabir
Amilcar
A
Flores-Morales
Lars
L
Rönnstrand
D020816:Amino Acid Motifs; D000818:Animals; D004789:Enzyme Activation; D006728:Hormones / Q000502:physiology; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000502:physiology; D009369:Neoplasms / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D018121:Receptors, Cytokine / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D050826:Suppressor of Cytokine Signaling Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000502:physiology; D018909:src Homology Domains
D006728:Hormones; D009363:Neoplasm Proteins; D018121:Receptors, Cytokine; D050826:Suppressor of Cytokine Signaling Proteins; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D020794:Receptor Protein-Tyrosine Kinases