Cell signaling: An overview

Signal transduction is one of the fundamental processes of living cells being second in importance only to cell division. From the unicellular organism to multicellular organism, evolution has molded a diverse array of novel motifs and mechanisms to ensure that cells can eciently adapt to their environment. A multitude of signaling circuits has evolved to process the signals involved in extra-, intraand inter-cellular communications. Cells respond to some types of signals by starting to proliferate, to others by initiating dierentiation, and to a few by committing themselves to die. Thus, the signaling mechanisms that are present in a cell play a major role in all phases of its life. A basic biological signaling unit consists of three distinct functional components: a signal-receiver/discriminator, a signaltransducer, and a signal-ampli®er. A schematic picture of cell signaling pathways often depicts these functional components as being organized as dierent discrete signaling units, each of them involved in a speci®c pathway. However, recent studies from several laboratories have broadened this view. The emerging map of the signaling pathways identi®es a myriad of molecules that interact and interface with dierent signaling pathways to form a signaling network integrating multiple receptors, signal-transducers, and second messengers. The major theme of the collection of reviews presented here focuses on the mechanisms by which dierent receptors and signal-transducers regulate signal-integration to form the well coordinated signaling networks involved in cell proliferation, oncogenesis, and apoptosis. Each author traces this signaling-network from his/her own unique vantage point. Regulation of cell growth can be mediated by receptors belonging to dierent super families that include G protein-coupled receptors, receptor tyrosine kinases, cytokine receptors, cell adhesion receptors, and antigen receptors. Cell signaling mechanisms that originate from these diverse receptors are presented in the ®rst four articles of this issue. Although the authors of these articles look at signaling from its origin (i.e. cell surface receptors), by no means are their views limited to receptors alone. In fact, all of these articles trace the signaling routes from the cell surface receptors to the nuclear events leading to cell proliferation through the maze of small GTPases, kinase signaling-modules, non-receptor tyrosine kinases, and transcription factors. In the ®rst article, Silvio Gutkind describes the diverse mechanisms by which G protein-coupled receptors (GPCRs) mediate signal transduction and signal integration to promote cell growth. In the next article, Porter and Vaillancourt recount the mechanisms through which the receptor tyrosine kinase accomplishes the same goal by recruiting both similar and dierent sets of signaling molecules. In another article Tamir and Cambier describe how antigen receptors transmit signals primarily by using the non-receptor tyrosine kinases belonging to the Src-family of non receptor kinases. Cell proliferation, dierentiation, and apoptosis often involve changes in cell adhesion properties and modulation of cell volume and cell shape. Integrin receptors play a cardinal role in regulating the cytoskeletal responses involved in these processes. In his review, Chandra Kumar narrates the various signaling mechanisms through which the integrin receptors modulate dierent cytoskeletal components. As highlighted by these reviews, it is interesting to note that the diverse signaling pathways regulated by the respective receptors utilize unique as well as overlapping sets of signaling molecules. While the unique sets of regulatory molecules insulate the respective signaling pathway from the `noise' of adjacent pathways, the overlapping sets of regulatory molecules (such as small GTPases, tyrosine kinases, and kinase signaling-modules) integrate cell signaling between these dierent signaling pathways. The next series of articles describe molecular mechanisms mediated by `signal insulators' and `signal integrators.' Signaling by the heterotrimeric G proteins appears to be predominantly used by the GPCRs whereas small GTPase such Ras, Rac, and Rho are universally used by many dierent receptor systems. Therefore, to a certain extent, one can categorize the heterotrimeric G proteins as signal insulators and the small GTPase as signal integrators. The critical and unique signaling roles played by the dierent a-subunits of the heterotrimeric G proteins are detailed in the article presented by Oermanns and Simon. In this review, the authors describe the role of individual a-subunits in regulating both developmental and behavioral responses derived from the recently carried-out gene knock-out studies from several laboratories including theirs. In the following article, the possible mechanisms by which the aand the bg-subunits of the heterotrimeric G proteins regulate small GTPases and non-receptor kinases, thus interfacing with the signaling-modules that are activated by receptor tyrosine kinases are described. All these reviews unequivocally point to the Rasand Rhofamily of small GTPases as the critical signaling terminals through which signals to dierent target-destinations are shuttled and relayed through other signaling modules. Channing Der and his colleagues, in two articles, describe how the diverse mechanisms by which Rasand Rho-family of GTPases virtually regulate all the phases of cell growth. Not surprisingly, being such an essential conduit for multiple signaling pathways, these Oncogene (1998) 17, 1329 ± 1330  1998 Stockton Press All rights reserved 0950 ± 9232/98 $12.00