Signaling by Kit protein-tyrosine kinase--the stem cell factor receptor.

Article Details

Citation

Copy to clipboard

Roskoski R Jr

Signaling by Kit protein-tyrosine kinase--the stem cell factor receptor.

Biochem Biophys Res Commun. 2005 Nov 11;337(1):1-13.

PubMed ID

16129412 [ View in PubMed

]

Abstract

Signaling by stem cell factor and Kit, its receptor, plays important roles in gametogenesis, hematopoiesis, mast cell development and function, and melanogenesis. Moreover, human and mouse embryonic stem cells express Kit transcripts. Stem cell factor exists as both a soluble and a membrane-bound glycoprotein while Kit is a receptor protein-tyrosine kinase. The complete absence of stem cell factor or Kit is lethal. Deficiencies of either produce defects in red and white blood cell production, hypopigmentation, and sterility. Gain-of-function mutations of Kit are associated with several human neoplasms including acute myelogenous leukemia, gastrointestinal stromal tumors, and mastocytomas. Kit consists of an extracellular domain, a transmembrane segment, a juxtamembrane segment, and a protein kinase domain that contains an insert of about 80 amino acid residues. Binding of stem cell factor to Kit results in receptor dimerization and activation of protein kinase activity. The activated receptor becomes autophosphorylated at tyrosine residues that serve as docking sites for signal transduction molecules containing SH2 domains. The adaptor protein APS, Src family kinases, and Shp2 tyrosyl phosphatase bind to phosphotyrosine 568. Shp1 tyrosyl phosphatase and the adaptor protein Shc bind to phosphotyrosine 570. C-terminal Src kinase homologous kinase and the adaptor Shc bind to both phosphotyrosines 568 and 570. These residues occur in the juxtamembrane segment of Kit. Three residues in the kinase insert domain are phosphorylated and attract the adaptor protein Grb2 (Tyr703), phosphatidylinositol 3-kinase (Tyr721), and phospholipase Cgamma (Tyr730). Phosphotyrosine 900 in the distal kinase domain binds phosphatidylinositol 3-kinase which in turn binds the adaptor protein Crk. Phosphotyrosine 936, also in the distal kinase domain, binds the adaptor proteins APS, Grb2, and Grb7. Kit has the potential to participate in multiple signal transduction pathways as a result of interaction with several enzymes and adaptor proteins.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Mast/stem cell growth factor receptor Kit	P10721	Details
Growth factor receptor-bound protein 2	P62993	Details
Protein kinase C alpha type	P17252	Details
Tyrosine-protein kinase Lyn	P07948	Details
Megakaryocyte-associated tyrosine-protein kinase	P42679	Details
Tyrosine-protein phosphatase non-receptor type 6	P29350	Details