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Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand
Y Yarden1, W J Kuang, T Yang-Feng
1Department of Developmental Biology, Genentech, Inc., South San Francisco 94080.
Abstract:
Structural features of v-kit, the oncogene of HZ4 feline sarcoma virus, suggested that this gene arose by transduction and truncation of cellular sequences. Complementary DNA cloning of the human proto-oncogene coding for a receptor tyrosine kinase confirmed this possibility: c-kit encodes a transmembrane glycoprotein that is structurally related to the receptor for macrophage growth factor (CSF-1) and the receptor for platelet-derived growth factor. The c-kit gene is widely expressed as a single, 5-kb transcript, and it is localized to human chromosome 4 and to mouse chromosome 5. A c-kit peptide antibody permitted the identification of a 145,000 dalton c-kit gene product that is inserted in the cellular plasma membrane and is capable of self-phosphorylation on tyrosine residues in both human glioblastoma cells and transfected mouse fibroblasts. Our results suggest that p145c-kit functions as a cell surface receptor for an as yet unidentified ligand. Furthermore, carboxy- and amino-terminal truncations that occurred during the viral transduction process are likely to have generated the transformation potential of v-kit.
Insights
The c-kit proto-oncogene encodes a cell surface receptor tyrosine kinase. This receptor, p145c-kit, is implicated in cell growth and is structurally similar to other growth factor receptors.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- The v-kit oncogene, derived from feline sarcoma virus, shows structural similarities to cellular genes.
- Proto-oncogenes can be activated through viral transduction and truncation.
Purpose of the Study:
- To clone and characterize the human proto-oncogene homologous to v-kit.
- To investigate the structure, expression, and function of the c-kit gene product.
Main Methods:
- Complementary DNA (cDNA) cloning of the human c-kit gene.
- Gene localization studies using human and mouse chromosomes.
- Peptide antibody generation for c-kit protein identification.
- Analysis of c-kit protein expression and phosphorylation in cell lines.
Main Results:
- c-kit encodes a transmembrane glycoprotein receptor tyrosine kinase, structurally related to CSF-1 and PDGF receptors.
- The c-kit gene is expressed as a 5-kb transcript and located on human chromosome 4 and mouse chromosome 5.
- A 145,000 dalton c-kit protein (p145c-kit) was identified in the plasma membrane, exhibiting tyrosine autophosphorylation.
Conclusions:
- p145c-kit functions as a cell surface receptor, likely for an unknown ligand.
- Truncations in the viral v-kit oncogene are responsible for its transforming potential.