Primary structure of c-kit: relationship with the CSF-1/PDGF receptor kinase family-oncogenic activation of v-kit involves deletion of extracellular domain and C terminus.

Abstract

The protein kinase domains of v‐kit, the oncogene of the acute transforming feline retrovirus HZ4‐FeSV (HZ4‐feline sarcoma virus), CSF‐1R (macrophage colony stimulating factor receptor) and PDGFR (platelet derived growth factor receptor) display extensive homology. Because of the close structural relationship of v‐kit, CSF‐1R and PDGFR we predicted that c‐kit would encode a protein kinase transmembrane receptor (Besmer et al., 1986a; Yarden et al., 1986). We have now determined the primary structure of murine c‐kit from a DNA clone isolated from a brain cDNA library. The nucleotide sequence of the c‐kit cDNA predicts a 975 amino acid protein product with a calculated mol. wt of 109.001 kd. It contains an N‐terminal signal peptide, a transmembrane domain (residues 519‐543) and in the C‐terminal half the v‐kit homologous sequences (residues 558‐925). c‐kit therefore contains the features which are characteristic of a transmembrane receptor kinase. Comparison of c‐kit, CSF‐1R and PDGFR revealed a unique structural relationship of these receptor kinases suggesting a common evolutionary origin. The outer cellular domain of c‐kit was shown to be related to the immunoglobulin superfamily. The sites of expression of c‐kit in normal tissue predict a function in the brain and in hematopoietic cells. N‐terminal sequences which include the extracellular domain and the transmembrane domain as well as 50 amino acids from the C‐terminus of c‐kit are deleted in v‐kit. These structural alterations are likely determinants of the oncogenic activation of v‐kit.(ABSTRACT TRUNCATED AT 250 WORDS)

Elevated expression of the proto-oncogene c-kit in patients with mastocytosis

“…1,2 The common structural feature of this family of receptors is a five immunoglobulin-like loop structure in the extracellular domain and a kinase insert which splits the catalytic domain between the ATP binding site and the phosphotransferase active site. In human c-kit, there are two kinds of isoforms which are generated by alternative splicing.…”

Immunohistochemical expression of the c-kit proto-oncogene product in human malignant and non-malignant breast tissues

“…The c-kit proto-oncogene encodes a transmembrane tyrosine kinase receptor with a molecular weight of 145 000 Da, which is structurally similar to the platelet-derived growth factor receptor and the colony-stimulating factor-I receptor (Qiu et al, 1988). Recent studies have demonstrated that the c-kit proto-oncogene product is expressed in a restricted number of human fetal, adult tissues and solid tumours (Natali et al, 1992a;Matsuda et al, 1993).…”

Specific and common activities of the FLT3 and KIT tyrosine kinase receptors revealed by the use of cultured mast cells

“…For the class III receptor tyrosine kinases (RTK), signal transduction involves the participation of intrinsic protein tyrosine kinase activity. 1 FLT3 2,3 and KIT 4,5 belong to the class III RTK; they encode the receptors for FL (FLT3 ligand) and for SCF/KL (stem cell factor/KIT ligand) respectively. 6 Ectopical expression of a receptor in a cellular environment physiologically associated to a closely related receptor, is a potential way to define shared transduction pathways between these two receptors.…”