Andrew Chan

Growth Factors and Malignant Transformation

In the early 1980’s, approaches aimed at identifying the functions of retroviral oncogenes converged with efforts to investigate normal mitogenic signaling by growth factors. A number of retroviral oncogene products were found to be similar to the protein kinase encoded by v-src product1. Unlike many protein kinases that phosphorylate serine or threonine residues, the v-src product is a protein kinase that specifically phosphorylates tyrosine residues2. Purification and sequencing of growth factors and their receptors revealed that the platelet derived growth factor (PDGF) B-chain is similar to the predicted v-sis oncogene product3 and that the v-erbB oncogene product, which has sequence similarity to the v-src product, is a truncated form of the EGF receptor4. Binding of EGF to its receptor results in autophosphorylation of the receptor on tyrosine5. Oncogenes activated by a variety of mechanisms6 frequently have been shown to encode growth factors, receptor tyrosine kinases or downstream effectors.

KGF Receptor: Transforming Potential on Fibroblasts and Epithelial Cell-Specific Expression by Alternative Splicing

The mouse keratinocyte growth factor (KGF) receptor (KGFR) cDNA was isolated by an expression cDNA cloning strategy involving creation of a transforming autocrine loop. Characterization of the cloned 4.2 kb cDNA revealed a predicted membrane-spanning tyrosine kinase structurally related to the FGF receptor (FGFR). Structural analysis of the human KGFR cloned by the analogous procedure revealed identity with one of the fibroblast growth factor (FGF) receptors (bek/FGFR-2) except for a divergent stretch of 49 amino acids in their extracellular domains. Binding assays demonstrated that the KGFR was a high affinity receptor for both KGF and acidic FGF, while FGFR-2 showed high affinity for basic FGF and acidic FGF but no detectable binding by KGF. Analysis of the bek gene revealed two alternative exons responsible for the region of divergence between the two receptors. The KGFR transcript was specific to epithelial cells, and it appeared to be differentially regulated with respect to the alternative FGFR-2 transcript.