Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Signals and Receptors Carl-Henrik Heldin1, Benson Lu2, Ron Evans2, and J. Silvio Gutkind3 1Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, SE-75124 Uppsala, Sweden 2The Salk Institute for Biological Studies, Gene Expression Laboratory, La Jolla, California 92037 3National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892-4340 Correspondence: [email protected] SUMMARY Communication between cells in a multicellular organism occurs by the production of ligands (proteins, peptides, fatty acids, steroids, gases, and other low-molecular-weight compounds) that are either secreted by cells or presented on their surface, and act on receptors on, or in, other target cells. Such signals control cell growth, migration, survival, and differentiation. Signaling receptors can be single-span plasma membrane receptors associated with tyrosine or serine/threonine kinase activities, proteins with seven transmembrane domains, or intra- cellular receptors. Ligand-activated receptors convey signals into the cell by activating signal- ing pathways that ultimately affect cytosolic machineries or nuclear transcriptional programs or by directly translocating to the nucleus to regulate transcription. Outline 1 Introduction 6 Functions of nuclear receptors 2 Cell-surface receptors 7 Gases 3 The TNF receptor family 8 Concluding remarks 4 Cell adhesion receptors and References mechanotransducers 5 Nuclear receptors Editors: Lewis Cantley, Tony Hunter, Richard Sever, and Jeremy Thorner Additional Perspectives on Signal Transduction available at www.cshperspectives.org Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a005900 Cite this article as Cold Spring Harb Perspect Biol 2016;8:a005900 1 Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press C.-H. Heldin et al. 1 INTRODUCTION immune system and also promote cell differentiation. Cy- tokine receptors can be divided into two classes. The ex- Cells within multicellular organisms need to communicate tracellular domains of class I cytokine receptors contain with each other to coordinate their growth, migration, cytokine receptor homology domains (CHDs) consisting survival, and differentiation. They do so by direct cell– of two tandem fibronectin type III domains with a charac- cell contact and secretion or release of molecules that teristic WSXWS motif in the second (Liongue and Ward bind to and activate receptors on the surface of or inside 2007). Based on the number of CHDs and the presence of target cells. Such factors can stimulate the producer cell other types of domains, the class I cytokine receptors can be itself (autocrine stimulation), cells in the immediate vicin- divided into five groups (Fig. 2), the growth hormone ity (paracrine stimulation), or cells in distant organs (en- (GH) receptor being typical of the first group. Interferon docrine stimulation). The signaling induced within target receptors are typical of the 12-member class II cytokine cells is important during embryonic development, as well receptor family, which also have extracellular regions based as in the adult, where it controls cell proliferation, differ- on tandem fibronectin domains but differ from those of entiation, the response to infection, and numerous organ- class I receptors (Fig. 2) (Renauld 2003). Both classes of ismal homeostatic mechanisms. cytokine receptors have conserved box 1 and box 2 regions Many cell-surface receptors contain an extracellular li- in their intracellular regions, which bind to JAK family gand-binding region, a single transmembrane segment, and tyrosine kinases that are activated upon ligand binding. an intracellular effector region, which may or may not have The multisubunit antigen receptors on B cells and T cells an associated enzyme activity. Some receptors contain (Zikherman and Weiss 2009) and the Fc receptors present multiple subunits that together form the ligand-binding on macrophages, mast cells, basophils, and other immune site. Others, including those encoded by the largest gene cells (Nimmerjahn and Ravetch 2008) are also associated family in the human genome, consist of a polypeptide with intracellular tyrosine kinases; activation of these re- that spans the cell membrane seven times. Finally, there ceptors involves tyrosine phosphorylation by members of are receptors that are located intracellularly and are acti- the Src family, followed by docking and activation of SH2- vated by ligands that cross the cell membrane, such as ste- domain-containing Syk/Zap70 tyrosine kinases (see Sa- roid hormones. Below, we describe the major families of melson 2011; Cantrell 2014). Although receptors that ligands and receptors and the signal transduction mecha- have intrinsic tyrosine kinase activity and those associated nisms they activate. with tyrosine kinases are structurally different and bind ligands of different kinds, the principles underlying their 2 CELL-SURFACE RECEPTORS activation and the intracellular signals they initiate are sim- ilar (see below). 2.1 Receptors with Associated Protein Kinase There is also a family of receptors that have intrinsic Activity serine/threonine kinase domains, and these respond to Several types of cell-surface receptors contain or are asso- members of the transforming growth factor b (TGFb) fam- ciated with kinase activities that respond to the binding of a ily (see Moustakas and Heldin 2009; Wrana 2013). The ligand. Perhaps best understood are receptors with intrinsic human genome has only 12 genes encoding receptors of protein tyrosine kinase domains. This receptor tyrosine this type (Fig. 3). These receptors have rather small cys- kinase (RTK) family has more than 50 human members teine-rich extracellular domains; their intracellular do- (Lemmon and Schlessinger 2010). RTKs have important mains are most often also small and consist mainly of the roles in the regulation of embryonic development, as well as kinase domains. TGFb receptors mediate signaling events in the regulation of tissue homeostasis in the adult. Each during embryonic development. Because they often inhibit has an extracellular, ligand-binding region, which consists cell growth, they also exert a controlling function on the of different combinations of various domains, such as Ig- immune system and other tissues. like, fibronectin type III, and cysteine-rich domains. This is linked to a single transmembrane segment and an intracel- lular region that includes a tyrosine kinase domain. Based 2.2 Ligands on their structural features, RTKs can be divided into 20 Each of these different receptor types responds to a sub- subfamilies (Fig. 1), a well-studied example being the epi- family of structurally similar ligands. The ligands are nor- dermal growth factor (EGF) receptors (EGFRs). mally small monomeric, dimeric, or trimeric proteins, Members of the cytokine receptor family in contrast often derived by proteolytic processing from larger precur- lack intrinsic kinase activity but associate with intracellular sors, some of which are transmembrane proteins. There is kinases. They have important roles in the regulation of the not a strict specificity in ligand–receptor interactions with- 2 Cite this article as Cold Spring Harb Perspect Biol 2016;8:a005900 Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Signals and Receptors EGFR InsR PDGFRα VEGFR1/ FGFR1 PTK7/ TrkA Rot1 MuSk Met AxI Tie1 EphA1-8 Ret Ryk DDR1 Ros LMR1 ALK SuRTK106/ ErbB2 IGF1R PDGFRβ FIt1 FGFR2 CCK4 TrkB Ror2 Ron Mer Tie2 EphA10 DDR2 LMR2 LTK STYK1 ErbB3 InsRR CSF1R/ VEGFR2/ FGFR3 TrkC Tyro3 EphB1-4 LMR3 ErbB4 Fms KDR FGFR4 EphB6 Kit/SCFR VEGFR3/ FIt3/FIk2 FIt4 Tyrosine L Cysteine- Fibronectin Leucine- Cadherin Discoidin Ig EGF-like Kringle kinase rich type III rich SAM Psi WIF Ephrin Fz Ldla YMTD Acid Sema Mam binding propeller box Figure 1. Receptor tyrosine kinase (RTK) families. The 20 subfamilies of human RTKs and their characteristic structural domains are shown. The individual members of each family are listed below. (From Lemmon and Schlessinger 2010; adapted, with permission.) in the families; normally each ligand binds to more than 2.3 Activation by Dimerization one receptor, and each receptor binds more than one li- A common theme for activation of kinase-associated recep- gand. Although it is rare that ligands for completely differ- tors is ligand-induced receptor dimerization or oligomeri- ent types of receptors bind to kinase-associated receptors, zation (Heldin 1995). The juxtaposition of the intracellular examples do exist.4 kinase domains that occurs as a consequence allows auto- phosphorylation in trans within the complex. For RTKs, the autophosphorylation has two important consequences: 4The Ryk and Ror families of RTK, for example, bind members of the Wnt it changes the conformation of the kinase domains, leading family. Ryk has a Wnt inhibitory factor-1 (WIF1) domain, and the two Ror to an increase in their kinase activities; and it produces receptors have cysteine-rich domains related to a domain in the Frizzled family of serpentine receptors to which ligands of the Wnt family bind docking sites (phosphorylated sequences) for intracellular (van Amerongen et al. 2008). signaling molecules containing