Cell Signaling: an Overview

N Dhanasekaran

Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 USA

Keywords: signal transduction; receptors; G proteins; recount the mechanisms through which the receptor GTPases; kinases; oncogenes tyrosine kinase accomplishes the same goal by recruiting both similar and dierent sets of signaling molecules. In another article Tamir and Cambier Signal transduction is one of the fundamental processes describe how antigen receptors transmit signals of living cells being second in importance only to cell primarily by using the non-receptor tyrosine kinases division. From the unicellular organism to multicellular belonging to the Src-family of non receptor kinases. organism, evolution has molded a diverse array of Cell proliferation, dierentiation, and apoptosis often novel motifs and mechanisms to ensure that cells can involve changes in cell adhesion properties and eciently adapt to their environment. A multitude of modulation of cell volume and cell shape. Integrin signaling circuits has evolved to process the signals receptors play a cardinal role in regulating the involved in extra-, intra- and inter-cellular communica- cytoskeletal responses involved in these processes. In tions. Cells respond to some types of signals by starting his review, Chandra Kumar narrates the various to proliferate, to others by initiating dierentiation, signaling mechanisms through which the integrin and to a few by committing themselves to die. Thus, receptors modulate dierent cytoskeletal components. the signaling mechanisms that are present in a cell play As highlighted by these reviews, it is interesting to note a major role in all phases of its life. A basic biological that the diverse signaling pathways regulated by the signaling unit consists of three distinct functional respective receptors utilize unique as well as over- components: a signal-receiver/discriminator, a signal- lapping sets of signaling molecules. While the unique transducer, and a signal-ampli®er. A schematic picture sets of regulatory molecules insulate the respective of cell signaling pathways often depicts these functional signaling pathway from the `noise' of adjacent path- components as being organized as dierent discrete ways, the overlapping sets of regulatory molecules signaling units, each of them involved in a speci®c (such as small GTPases, tyrosine kinases, and kinase pathway. However, recent studies from several signaling-modules) integrate cell signaling between laboratories have broadened this view. The emerging these dierent signaling pathways. The next series of map of the signaling pathways identi®es a myriad of articles describe molecular mechanisms mediated by molecules that interact and interface with dierent `signal insulators' and `signal integrators.' signaling pathways to form a signaling network Signaling by the heterotrimeric G proteins appears integrating multiple receptors, signal-transducers, and to be predominantly used by the GPCRs whereas small second messengers. The major theme of the collection GTPase such Ras, Rac, and Rho are universally used of reviews presented here focuses on the mechanisms by many dierent receptor systems. Therefore, to a by which dierent receptors and signal-transducers certain extent, one can categorize the heterotrimeric G regulate signal-integration to form the well coordinated proteins as signal insulators and the small GTPase as signaling networks involved in cell proliferation, signal integrators. The critical and unique signaling oncogenesis, and apoptosis. Each author traces this roles played by the dierent a-subunits of the signaling-network from his/her own unique vantage heterotrimeric G proteins are detailed in the article point. presented by Oermanns and Simon. In this review, Regulation of cell growth can be mediated by the authors describe the role of individual a-subunits in receptors belonging to dierent super families that regulating both developmental and behavioral re- include G protein-coupled receptors, receptor tyrosine sponses derived from the recently carried-out gene kinases, cytokine receptors, cell adhesion receptors, knock-out studies from several laboratories including and antigen receptors. Cell signaling mechanisms that theirs. In the following article, the possible mechanisms originate from these diverse receptors are presented in by which the a- and the bg-subunits of the the ®rst four articles of this issue. Although the authors heterotrimeric G proteins regulate small GTPases and of these articles look at signaling from its origin (i.e. non-receptor kinases, thus interfacing with the signal- cell surface receptors), by no means are their views ing-modules that are activated by receptor tyrosine limited to receptors alone. In fact, all of these articles kinases are described. All these reviews unequivocally trace the signaling routes from the cell surface point to the Ras- and Rho- family of small GTPases as receptors to the nuclear events leading to cell the critical signaling terminals through which signals to proliferation through the maze of small GTPases, dierent target-destinations are shuttled and relayed kinase signaling-modules, non-receptor tyrosine ki- through other signaling modules. Channing Der and nases, and transcription factors. In the ®rst article, his colleagues, in two articles, describe how the diverse Silvio Gutkind describes the diverse mechanisms by mechanisms by which Ras- and Rho-family of which G protein-coupled receptors (GPCRs) mediate GTPases virtually regulate all the phases of cell signal transduction and signal integration to promote growth. Not surprisingly, being such an essential cell growth. In the next article, Porter and Vaillancourt conduit for multiple signaling pathways, these Cell signaling: An overview NDhanasekaran 1330 GTPases have remained for many years as the and oncogenesis. However, it has been noticed that the potential targets of several drug discovery programs. deprivation of proliferative/survival signals or the The articles by Campbell et al. as well as Lebowitz and asynchronous activation of some of these signals have Prendergast discuss the probability of success in using been known to commit cells to programmed cell death these loci as therapeutic targets for drug discovery. or apoptosis. In addition, the novel family of death The small GTPases transmit their signals to the receptors such as Fas and Trail are speci®cally involved nucleus through sequentially phosphorylating kinases in the activation of apoptosis. While dierent sets of collectively known as kinase signaling-module. A signaling-molecules belonging to the BCL2-family of typical kinase-module consists of a central dual- proteins and caspases play a predominant role in speci®city kinase ¯anked by Ser/Thr kinases on its apoptotic signaling, it is noteworthy that the JNK- upstream and downstream. To date, only three distinct signaling module, especially the upstream kinase kinase-modules namely JNK-, ERK- and p38MAPK- MEKK, plays a major role in the initiation as well modules have been fully characterized in mammalian as the progression of apoptosis. In their article, Gary cells. However, the identi®cation of several dierent Johnson and his colleagues summarize these inter- isoforms of the constituent kinases of these signaling relationships between cell survival-, proliferative- and modules attest to the fact that there may be more apoptotic-pathways. In the last article, Ronai describes hitherto uncharacterized kinase-modules. The current how `targeted-ubiquitination' and degradation of state of our knowledge regarding these kinase signaling proteins can play a signi®cant role in cell signaling-modules is discussed in the article by signaling. Dhanasekaran and Reddy. Of these kinase modules, A critical survey of cell signaling often reveals the the archetypal kinase module is that of ERK. ERK- presence of functional and molecular redundancy along signaling module consists of a Ser/Thr kinase Raf, a with apparent co-incidental signaling, signaling cross- middle dual speci®city kinase MEK, and a downstream talk and signal overlapping. However, a closer look at kinase ERK (belonging to the family of MAP kinases). the individual signaling pathways as presented by the Raf, the upstream kinase in the ERK-module is authors in these articles indicates that the mechanisms predominantly activated by Ras through its physical involved in signal integration (between dierent path- interaction. Subsequent sequential phosphorylation of ways) is as important as the mechanism of signal the constituent kinases of the ERK module and the transduction. Considering the complex machinery activation of TCFs ultimately leads to cell prolifera- needed to be activated during the dierent phases of tion. Although the mechanism through which Ras cell growth, some of the observed co-incidental activates ERK-signaling module has been known for a signaling, signal overlapping, and molecular redun- while, only recent studies have indicated that signals dancy may be intended mechanisms involved in signal- from Raf-MEK-ERK module are translated into integration. Furthermore, the observations that the growth promotion via the activation of cell-cycle multiple eector molecules can be activated by a single proteins. The review by Kerkho and Rapp illustrates receptor and that the signals from dierent receptors the primary role played by Raf in integrating the can be integrated, substantiate the emerging view that signals from the growth factors to the cell cycle-speci®c multiple signaling-inputs are required for committing proteins. As described by Gutkind, Tamir and the cells to the critical pathways involved in cell Cambier, the Src family of tyrosine kinases plays a growth. From the reviews presented here, it appears critical role in transmitting the signals from diverse that the major players involved in the regulation of receptor families. Although the molecular interaction signal transduction and signal integration have been involved in Src-activation by these receptors still identi®ed. Consequently, in the near future we can remains to be fully resolved, the possible mechanisms expect a detailed map of signaling routes from the through which Src can interact with dierent cartographers of cell signaling. It is more likely that regulatory molecules are reviewed by Pamela Schwartz- such a detailed-map may ®nally provide us with the berg. In the same vein, a review by Marius Sudol location of the dierent `check points' for the describe the dierent molecular motifs in Src that may therapeutic intervention of diseases due to the hypo- assist it in its interaction with other signaling proteins. or hyper activity of the signaling molecules. Most of the foregoing discussions have focused on the signaling mechanisms involved in cell proliferation