Autophosphorylation

Protein kinases, many of which are regulated by autophosphorylation, are vital in controlling the cellular proliferation, differentiation, metabolism, migration and survival. Mutations in the genes encoding them or their potential activators or repressors can affect any number of functions within an organism. Binding of effector molecules may be affected in a similar manner if the phosphorylated residue makes part of the allosteric site. Autophosphorylation has also been reported to have an effect on the cell's ability for endocytosis and proteolysis. ==Process and structure==

Kinases are either phosphorylated on serine and/or threonine residues, or solely on tyrosine residues. The known structures include: • Tyr phosphorylation sites in juxtamembrane regions: • human cKIT, Tyr568 (PDB: 1PKG) • human CSF1R, Tyr561 (PDB: 3LCD, homologous to cKIT site) • human EPHA2, Tyr594 (PDB: 4PDO, two residues after the cKIT and CSF1R sites) • human FGFR3, Tyr577 (PDB: 4K33, homologous to the FGFR1 site, • Tyr phosphorylation sites in activation loops: • human IGF1R, Tyr1165 (PDB: 3D94) • human IGF1R, Tyr1166 (PDB: 3LVP) • human LCK, Tyr394 (PDB: 2PL0, homologous to the IGF1R Tyr1165 site • Ser/Thr phosphorylation sites in activation loops: • human PAK1, Thr423 (PDB: 3Q4Z, 4O0R, 4O0T, 4P90, 4ZLO, 4ZY4, 4ZY5, 4ZY6, 5DEY; the 4ZY4 and 4ZY5 structures provide complete coordinates for the substrate activation loop • human IRAK4, Thr345 (PDB: 4U97, 4U9A) • N or C terminal tails Ser/Thr phosphorylation sites: • C. elegans CaMKII, C-terminal tail, Thr284 (PDB: 3KK8, 3KK9) • human CaMKII, C-terminal tail, Thr287 (PDB: 2WEL, homologous to the C. elegans site) • human CLK2, N-terminal tail, Ser142 (PDB: 3NR9) In general, the structures of the phosphorylation of internal loops involve important domain-domain contacts that have been confirmed by site-directed mutagenesis, while the phosphorylation of positions in the N or C terminal tails more than 10 amino acids away from the kinase domain do not involve important domain-domain contacts away from the substrate binding site. ==Signaling pathways and trans-autophosphorylation==

Among a number of various molecules, Receptor Tyrosine Kinases (RTKs) play a critical role in transducing signals through a range of signaling pathways. All RTKs consists of an extracellular ligand binding region, a single transmembrane helix and a cytoplasmic region (the tyrosine kinase domain). Prior to ligand stimulation most RTKs present as a monomer on the surface of cells. Ligand binding to the extracellular domain induces dimerization. Dimerization of RTKs leads to autophosphorylation of tyrosine in the catalytic core of the dimer, and finally stimulation of the tyrosine kinase activity and cell signaling. It is thus an example of a trans-autophosphorylation reaction, where one receptor subunit of the dimer phosphorylates the other subunit. Examples of RTKs which undergo autophosphorylation Epidermal growth factor receptor An example of RTKs that undergo autophosphorylation is the Epidermal Growth Factor receptor (EGFR). EGFR was the first discovered example of RTKs. Following ligand binding, a conformational change occurs in the EGFR monomers. This leads to EGFR dimerization. Dimerization brings the two receptors into close proximity. This stimulates the kinase activity of EGFR, which leads to transautophosphorylation on multiple tyrosine residues in C-terminal end of the molecule. The phosphorylated tyrosine residue can then serve as a docking site for downstream signaling proteins. (Fig. 1). Insulin receptors Another example is the binding of insulin to insulin receptors. Once released into the bloodstream insulin can bind to receptors on the surface of cells in muscle or other tissues. This receptor is a protein with an (αβ)2 quaternary structure. The two large α-subunits are extracellular, while the smaller β-subunits have a transmembrane domain as well as extra-and intracellular domains. In the absence of insulin, the two intracellular domains of the β subunits are relatively distant. Binding with insulin triggers a conformational change in the receptor that brings them closer together. Each β subunit intracellular domain is a tyrosine kinase that phosphorylates its partner in the receptor. ==Cancer==

Src kinases The Src-family kinases are examples of proteins that utilize autophosphorylation to sustain their activated states. == See also ==