Tyrosine-protein kinase CSK

Tyrosine-protein kinase CSK also known as C-Src kinase or C-terminal Src kinase is an is_associated_with::enzyme that, in humans, is encoded by the CSK is_associated_with::gene. This enzyme phosphorylates is_associated_with::tyrosine residues located in the is_associated_with::C-terminal end of is_associated_with::Src-family kinases (SFKs) including SRC, is_associated_with::HCK, is_associated_with::FYN, LCK, is_associated_with::LYN and is_associated_with::YES1.

Function
This Non-receptor tyrosine-protein kinase plays an important role in the regulation of is_associated_with::cell growth, differentiation, migration and is_associated_with::immune response. CSK acts by suppressing the activity of the Src family of protein kinases by is_associated_with::phosphorylation of Src family members at a conserved C-terminal tail site in Src. Upon phosphorylation by other is_associated_with::kinases, Src-family members engage in is_associated_with::intramolecular interactions between the is_associated_with::phosphotyrosine tail and the is_associated_with::SH2 domain that result in an inactive conformation. To inhibit SFKs, CSK is then recruited to the plasma membrane via binding to transmembrane proteins or adapter proteins located near the plasma membrane and ultimately suppresses signaling through various surface receptors, including T-cell receptor (TCR) and B-cell receptor (BCR) by phosphorylating and maintaining inactive several effector molecules.

Role in development and regulation
Tyrosine-protein kinase CSK is involved in the following developmental, metabolic, and is_associated_with::signal transduction cascades:

is_associated_with::Adherens junction organization, blood coagulation, brain development, cell differentiation, cell migration, cellular response to peptide hormone stimulus, central nervous system development, epidermal growth factor receptor signaling pathway, innate immune response, epithelium is_associated_with::morphogenesis, regulation of is_associated_with::bone resorption, negative regulation of cell proliferation, negative regulation of is_associated_with::ERK1 and is_associated_with::ERK2 cascade, negative regulation of Golgi to plasma membrane protein transport, negative regulation of is_associated_with::interleukin-6 production, negative regulation of kinase activity, negative regulation of is_associated_with::low-density lipoprotein particle clearance, negative regulation of is_associated_with::phagocytosis, dendrocyte differentiation, peptidyl-tyrosine autophosphorylation, platelet activation, positive regulation of is_associated_with::MAP kinase activity, regulation of cell proliferation, regulation of is_associated_with::cytokine production, regulation of is_associated_with::Fc receptor mediated stimulatory signaling pathway, is_associated_with::T cell costimulation, is_associated_with::T cell receptor signaling pathway.

Expression and subcellular location
CSK is expressed in the lungs and macrophages as well as several other tissues. Tyrosine-Kinase CSK is mainly mainly present in the cytoplasm, but also found in lipid rafts making cell-cell junction.

Mutations

 * Y184F – Abolishes is_associated_with::phosphorylation.
 * Y304F – Decreases activity by two-thirds and alters conformation.
 * S364A – Strong decrease of phosphorylation by is_associated_with::PRKACA (the catalytic subunit of is_associated_with::protein kinase A).

Clinical significance
Csk's interaction with a phosphatase ("Lyp", gene product of is_associated_with::PTPN22) is possibly associated with the increased is_associated_with::autoimmune diseases associated with is_associated_with::PTPN22 mutations.