Role of the Time Factor in Signaling Specificity: Application to Mitogenic and Metabolic Signaling by the Insulin and Insulin-Like Growth Factor-I Receptor Tyrosine Kinases Pierre De Meyts, Claus T. Christoffersen, Birgitte Urso, Brenda Wallach, Karen Gronskov, Fumiatsu Yakushiji, and Ronald M. Shymko The signal transduction pathways activated by hormones, growth factors, and cytokines show an extraordinary degree of cross-talk and redundancy. This review addresses the question of how the specificity conferred at the binding step is maintained through the signaling network despite the convergence of multiple signals on common efferent pathways such as mitogen-activated protein (MAP) kinase. The mechanism of receptor activation by ligand-induced dimerization provides a signaling device with both a switch and a timer. The role of the time factor, ie, of signaling kinetics, as a determinant of selectivity is discussed with emphasis on the receptor tyrosine kinases and cytokine receptors, and especially mitogenic versus metabolic signaling by insulin and insulin-like growth factor-I (IGF-I). Copyright © 1995 by W.B. Saunders Company H ORMONES and growth factors exert their intracellu- lar effects through the activation of a complex array of signaling pathways that are closely interconnected (see review by Seedorf in this issue). Although the starting point in the signaling cascades, the cell membrane-bound recep- tor, is highly specific for a given ligand (and sometimes a small number of closely related molecules), this apparent molecular selectivity is rapidly lost in the next steps of the signaling network given the convergence of multiple recep- tor-initiated signals on common pathways such as the ras/raf/MAPK/ERKkinase (MEK)/mitogen-activated pro- tein (MAP) kinase cascade or the phosphatidylinositol-3 kinase (for review, see De Meyts et al, 1 and Seedorf, this issue). Moreover, cross-talk between the pathways trig- gered by cytokine receptors, receptor tyrosine kinases, and seven-transmernbrane-domain receptors further compli- cates the understanding of how a specific starting signal travels through the network to generate a specific end-point pattern of cellular responses. Although a number of ele- ments are involved in the selectivity of signals (see below), this brief review will focus on the importance of the kinetic aspects (eg, transient v sustained) of the activation of signaling molecules, including the receptors themselves, in deciding which of multiple possible bifurcating pathways will actually be followed. CELLULAR PROTEIN KINASES The activity of a large number of cellular proteins is regulated through their reversible phosphorylation by en- zymes called protein kinases, 2 which transfer the third (g) phosphate of the cellular energy carrier adenosine triphos- phate to an amino acid side-chain containing a hydroxyl (OH) group. Most protein kinases, of which there may be more than 1,000, 3 phosphorylate proteins on serine or threonine. In contrast, the enzymes encoded by oncogenes From the Departments of Molecular Signaling and Scientific Computing, Hagedorn Research Institute, Gentofle, Denmark. Address reprint requests to Pierre De Meyts, MD, PhD, Hagedom Research Institute, Niels Steensens Vej 6, DK 2820 Gentofle, Den- mark. Copyright © 1995 by W..B. Saunders Company 0026-0495 / 95/4410-4002503. O0/0 such as the prototypical src, 4 as well as a number of growth factor receptors, instead phosphorylate tyrosines. Although tyrosine phosphorylation may represent less than 0.1% of total cellular phosphorylation events, it plays a crucial role in the control of normal cell growth (both early and late mitogenic events) and cell transformation, as well as in a number of metabolic signaling pathways. The reverse reaction, protein dephosphorylation, is equally important in cell regulation, and involves a vast array of phosphoprotein phosphatases with either serine/ threonine or tyrosine specificity that will not be discussed here (for review, see Hunter, 5 Cohen, 6 and Tonks et a17). Members of the protein tyrosine kinase family show considerable structural diversity: the conserved catalytic domain is combined with a wide variety of extracatalytic, regulatory domains (some of which are receptor-binding domains for extracellular ligands), s There are indeed two groups of protein tyrosine kinases: the nonreceptor, cyto- solic tyrosine kinases, and the transmembrane, receptor tyrosine kinases. 9 Several families of cytosolic kinases have been identified and many members molecularly cloned that are not recep- tors, such as the src, fes, abl, and JAK families.8 Some modules of src molecular anatomy, the so-called src homol- ogy (SH) domains SH2 and SH3, are found in other unrelated signaling molecules, where they play an impor- tant role in their binding to motifs containing phosphory- lated tyrosines (SH2) or proline-rich motifs (SH3) on activated protein tyrosine kinases or intermediary docking molecules. Many of the cytosolic tyrosine kinases are activated by growth factors and other cellular activators. 1° Upon activation, some of these kinases are recruited to the plasma membrane and associate with a non-tyrosine kinase receptor to become part of its signaling complex, eg, JAK2 with the growth hormone receptor. 11 OVERVIEW OF THE SUPERFAMILY OF RECEPTOR PROTEIN TYROSINE KINASES The members of this family receive environmental infor- mation from regulatory domains expressed on the cell surface. 12These receptors are allosteric molecules in which high-affinity ligand binding outside the cell induces confor- mational changes that activate the intracellular kinase 2 Metabolism, Vo144, No 10, Suppl4 (October), 1995: pp 2-11