G-Protein-Linked Receptors as Tyrosine Kinase Substrates: New Paradigms in Signal Integration

Understanding how cells integrate signals from a variety of chemically diverse information-containing molecules into complex, orchestrated responses such as cell proliferation, differentiation and apoptosis is an overarching goal of cell biology. The ligand molecules that act upon cell surface receptors include those mediating proximal aspects of signal transduction through two major pathways: those that are G protein linked and those that are tyrosine kinase linked. G-protein receptors in the hundreds operate by means of less populous groups of heterotrimeric G proteins and the effectors regulated by G proteins. Growth factor receptors with intrinsic tyrosine kinase activity constitute a relatively large group of receptors, which share several downstream signalling elements with the G-protein-linked receptors. Integration between these two dominant pathways has been obvserved at several levels. The most proximal and intimate interaction possible—that between G-protein-linked receptors and tyrosine kinase receptors—has been discovered. Emerging data reveal new paradigms in which phosphorylation of G-protein-linked receptors on specific tyrosyl residues by tyrosine kinases enable G-protein-linked receptors to interact with adaptor molecules and enzymes previously thought to be restricted only to the signalling derivative of tyrosine kinase receptors.