The juxtamembrane regions of the epidermal growth factor receptor and gpl 85erbB-2 determine the specificity of signal transduction

The epidermal growth factor receptor (EGFR) and gpl`5erbB"2 are closely related tyrosine kinases. Despite extensive sequence and structural homology, these two receptors display quantitative and qualitative differences in their ability to couple with mitogenic signalling pathways. By using chimeric molecules between EGFR and erbB-2, we found that the determinants responsible for the specificity of mitogenic signal transduction are located in the amino-terminal half of the tyrosine kinase domain of either receptor. In the EGFR, mutational analysis within this subdomain revealed that deletion of residues 660 to 667 impaired receptor mitogenic activity without affecting its tyrosine kinase properties. This sequence is therefore likely to contribute to the specificity of substrate recognition by the EGFR kinase. Many growth factors regulate cellular growth, metabo-lism, and differentiation through activation of receptors endowed with intrinsic tyrosine kinase activity (1, 37, 44, 45). These receptors possess an extracellular ligand-binding domain; a hydrophobic domain, which anchors the receptor to the plasma membrane; and an intracellular portion, con-taining the tyrosine kinase domain (TK), which shows goo