Switching Signals On or Off by Receptor Dimerization

mechanisms (Thomas and Brugge, 1997). Receptor PTKs are comprised of an extracellular ligand-binding domain, a single transmembrane domain, and a cytoArthur Weiss* and Joseph Schlessinger# *Departments of Medicine, Microbiology and Immunology Howard Hughes Medical Institute plasmic portion containing the catalytic core, as well as regulatory sequences. Several families of growth factors University of California, San Francisco San Francisco, California 94143-0795 induce receptor dimerization by virtue of their dimeric nature (e.g., PDGF). Monomeric growth factors, such as #Department of Pharmacology and the Skirball Institute EGF, contain two binding sites for their receptors and, therefore, can cross-link two neighboring EGF receptors New York University Medical Center New York, New York 10016 (Lemmon et al., 1997). Yet, another family of growth factors (FGF) bind to their receptors monovalently but utilize accessory molecules to facilitate the formation Many extracellular signals transduce their cellular responses by regulating the tyrosine phosphorylation of of multimeric ligand–receptor complexes (reviewed by Schlessinger, 1997). Receptor dimerization is essential target proteins. Protein tyrosine kinases (PTKs) can be divided into two classes of enzymes: receptor PTKs that for stimulation of the intrinsic catalytic activity and for the autophosphorylation of growth factor receptors. span a membrane, and cytoplasmic PTKs. Conversely, the dephosphorylation reaction of tyrosine phosphoryMoreover, receptor PTKs are able to undergo both homoand heterodimerization. Ligand-induced receplated proteins is carried out by protein tyrosine phosphatases (PTPs). PTPs can also be divided into two classes tor oligomerization has been established as a universal mechanism for the activation of hormone and growth of enzymes: transmembrane receptor-like PTPs, and cytoplasmic PTPs. Considerable progress has been factor receptors, lymphokine receptors, T-cell receptors, and B-cell receptors, as well as many other families made in understanding the regulation and activation of PTKs. In contrast, very little is known about the regulaof cell surface receptors (Lemmon and Schlessinger, 1994). Since eachprotomer in such oligomers can recruit tion and activity of PTPs, although a few clues are emerging from recent structural and functional studies. a distinct complement of signaling proteins, receptor oligomerization not only leads to increased catalytic Some of the paradigms learned from studying the PTKs have guided us well in our efforts toward understanding function but also provides a simple mechanism for generation of signal diversity (Lemmon and Schlessinger, PTP function. However, some surprising differences are also suggested. 1994). The mechanism by which receptor PTK dimerization Regulation of Protein Tyrosine Kinases It is now well established that receptor PTKs are actistimulates catalytic activity is not yet fully understood, but a picture from the available data is emerging (Hubvated by an intermolecular mechanism (Lemmon and Schlessinger, 1994). Cytoplasmic PTKs, on the other bard et al., 1998). Central to the activation of most PTKs is the phosphorylation of one or more tyrosines within hand, are activated by both intraand intermolecular