SOCS7 is a member of the suppressor of cytokine signaling family of proteins. SOCS7 functions in insulin signaling and glucose homeostasis through IRS1 ubiquitination and subsequent proteasomal degradation []. SOCS7 inhibits also prolactin, growth hormone and leptin signaling by preventing STAT3 and STAT5 activation, sequestering them in the cytoplasm and reducing their binding to DNA [].
SOCS7 is a member of the suppressor of cytokine signaling family of proteins. SOCS7 functions in insulin signaling and glucose homeostasis through IRS1 ubiquitination and subsequent proteasomal degradation []. SOCS7 inhibits also prolactin, growth hormone and leptin signaling by preventing STAT3 and STAT5 activation, sequestering them in the cytoplasm and reducing their binding to DNA [].This entry represents the SH2 domain of SOCS7.
This entry includes F-box only protein 30 (Fbxo30) []and F-box only protein 40 (Fbxo40) []. Fbxo30 is a ubiquitin ligase required for muscle loss, hence it is also known as muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1) []. Fbxo40 id an E3 ubiquitin ligase that induces IRS1 ubiquitination and breakdown specifically in skeletal muscle cells and only upon IGF1 (insulin-like growth factor 1) stimulation [].
This entry represents the SOCS box domain of SOCS7.SOCS7 is a member of the suppressor of cytokine signaling family of proteins. SOCS7 functions in insulin signaling and glucose homeostasis through IRS1 ubiquitination and subsequent proteasomal degradation []. SOCS7 inhibits also prolactin, growth hormone and leptin signaling by preventing STAT3 and STAT5 activation, sequestering them in the cytoplasm and reducing their binding to DNA [].The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions [, ].
ALK tyrosine kinase receptor (also known as anaplastic lymphoma kinase, ALK) is a neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system [].ALK transduces signals from ligands at the cell surface, through specific activation of the mitogen-activated protein kinase (MAPK) pathway. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1 [, , ]. ALK acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation [, ]. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis []. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [].This entry represents the insulin receptor, as well as related insulin-like receptors. The insulin receptor binds insulin and has a tyrosine-protein kinase activity, and mediates the metabolic functions of insulin. Binding to insulin stimulates the association of the receptor with downstream mediators, including IRS1 and phosphatidylinositol 3'-kinase (PI3K). The insulin receptor can activate PI3K either directly by binding to the p85 regulatory subunit, or indirectly via IRS1. When the insulin receptor is present in a hybrid receptor with IGF1R (insulin growth factor receptor), it binds IGF1 (insulin growth factor 1) [, , ].
