The receptors for mesenchymal growth factors contain tyrosine kinase coding sequences and exhibit ligand-activated tyrosine kinase activity. A variety of mutations of the epidermal growth factor, insulin and platelet-derived growth factor (PDGF) (manuscript in preparation) receptors that have resulted in a loss of tyrosine kinase activity have produced a concomitant loss of growth factor-stimulated DNA synthesis. Comparison of amino acid sequences of tyrosine kinases shows that these regions in the PDGF receptors in mouse and human contain an insert of unknown function. We have deleted this region, and expressed the altered form of the receptor in fibroblasts which lack PDGF receptors. This had no effect on a number of responses to PDGF, but cells bearing the mutant receptor did not proliferate or synthesize DNA in response to PDGF. This demonstrates that the insert is essential in PDGF-induced mitogenesis, and that PDGF stimulation of the mutant receptor tyrosine kinase and phosphatidylinositol turnover are not sufficient to elicit a mitogenic response to PDGF.