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.
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)
Qiu
F H
FH
Laboratory of Molecular Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Ray
P
P
Brown
K
K
Barker
P E
PE
Jhanwar
S
S
Ruddle
F H
FH
Besmer
P
P
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002415:Cats; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D004247:DNA / Q000235:genetics; D005786:Gene Expression Regulation; D005796:Genes; D006801:Humans; D006822:Hybrid Cells / Q000166:cytology; D051379:Mice; D008969:Molecular Sequence Data; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011519:Proto-Oncogenes; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D018719:Erb-b2 Receptor Tyrosine Kinases; D011956:Receptors, Cell Surface / Q000235:genetics*; D016184:Receptors, Colony-Stimulating Factor; D017479:Receptors, Platelet-Derived Growth Factor; D012190:Retroviridae / Q000235:genetics*
D004247:DNA; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D012313:RNA; D018719:Erb-b2 Receptor Tyrosine Kinases; D011956:Receptors, Cell Surface; D016184:Receptors, Colony-Stimulating Factor; D017479:Receptors, Platelet-Derived Growth Factor