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Receptor Tyrosine Kinases: Legacy of the First Two Decades

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Receptor Tyrosine Kinases: Legacy of the First Two Decades Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Receptor Tyrosine Kinases: Legacy of the First Two Decades Joseph Schlessinger Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520 Correspondence: [email protected] Receptor tyrosine kinases (RTKs) and their cellular signaling pathways play important roles in normal development and homeostasis. Aberrations in their activation or signaling leads to many pathologies, especially cancers, motivating the development of a variety of drugs that block RTK signaling that have been successfully applied for the treatment of many cancers. As the current field of RTKs and their signaling pathways are covered byavery large amount of literature, spread over half a century, I am focusing the scope of this review on seminal discoveries made before tyrosine phosphorylation was discovered, and on the early days of research into RTKs and their cellular signaling pathways. I review the history of the early days of research in the field of RTKs. I emphasize key early findings, which provided con- ceptual frameworks for addressing the questions of how RTKs are activated and how they regulate intracellular signaling pathways. he familyof cell-surface receptors designated sulting homogenous preparations of pure insu- Treceptor tyrosine kinases (RTK) received lin enabled the quantitative characterization of their name more that a decade after the same insulin binding to its receptor on intact cells or molecules were already known as the cell-sur- to solubilized insulin receptor preparations us- face receptors for insulin (insulin receptor), epi- ing radiolabeled insulin (De Meyts et al. 1973). dermal growth factor (EGFR), and many other These studies greatly advanced understanding growth factor receptors. Following the pioneer- of the ligand binding characteristics of insulin ing discoveries of nerve growth factor and epi- receptor and, later on EGFR (Carpenter et al. dermal growth factor (EGF; Levi-Montalcini 1975), including the establishment of negative and Booker 1960; Cohen 1962) and the estab- cooperativity in insulin binding to its receptor lishment of the important roles of these two expressed on the surface of living cells (De growth factors in the control of neuronal differ- Meyts et al. 1973). Moreover, these studies entiation and cell proliferation in vivo and in shed important light on the dynamic nature vitro, it became clear that these cytokines bind of the cellular behavior of these receptors. The specifically to cell-surface receptors. Insulin had capacities of insulin receptor and EGFR to un- already been discovered by this time, and had dergo ligand-dependent down-regulation and been applied successfully to treat diabetes pa- desensitization through receptor-mediated in- tients since the early twentieth century. The re- ternalization and degradation (Carpenter and Editors: Joseph Schlessinger and Mark A. Lemmon Additional Perspectives on Signaling by Receptor Tyrosine Kinases available at www.cshperspectives.org Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a008912 Cite this article as Cold Spring Harb Perspect Biol 2014;6:a008912 1 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press J. Schlessinger Cohen 1976; Gordon et al. 1978; Schlessinger conditions such as cancer. Early studies in the et al. 1978a,b; Carpentier et al. 1979; Haigler 1960s and 1970s showed that growth factors play et al. 1979) were also established well before an important role in oncogenesis induced by the realization that growth factors receptors retroviruses and in the proliferation of tumor- are endowed with intrinsic protein tyrosine ki- derived cancer cells. Pioneering studies per- nase activities (Fig. 1). formed by Howard Temin (1966, 1967) showed Progress was also made in elucidating the that cancer cells need less insulin and serum role of growth factors in normal embryonic de- growth factors for cell proliferation compared velopment, wound healing, and pathological with normal cells, suggesting that cancer cells 1986 1992 1980 - HGF discovered - Sem5 and Grb2 link PTKs to Ras - Neu is cloned and has - Individual PTK autophosphoryla- - Src is a protein tyrosine kinase activating point mutation tion sites bind distinct SH2 proteins (PTK) - Insulin receptor and PDGF - Stat transcription factors are - EGF signaling involves PTK receptor are cloned activated by Tyr phosphorylation activity 1973 - C-KIT is cloned - Jak family kinases required for - TGF-α discovered - Negative cooperativity in cytokine signaling via stat proteins insulin binding to insulin - Autocrine secretion and cell α - Structures of SH2 and SH3 domains receptor transformation by TGF- 1984 determined - v-erbB is derived from the 1994 EGF receptor 1990 1978 - EGF receptor cloned - Structure of tyrosine 1960s - EGF receptor gene is - SH2 domains bind phosphatases determined - FGF discovered - Structure of PH domains - EGF and NGF discovered amplified and mutated in P.Tyr-containing proteins - EGF and insulin γ determined - Cancer cells need less growth cancers - Phospholipase C is stimulated undergo receptor- - Structure of insulin receptor factors for proliferation by Tyr phosphorylation mediated internalization - MAP kinase cloned kinase domain determined 1960 1970 1980 1990 1970s 1979 1985 1991 - c-Fms encodes for CSF-1 receptor - Met is HGF receptor - Insulin, NGF, and EGF - PDGF discovered - Met discovered - Trk is NGF receptor bind to cell-surface - A dimerization model - Insulin receptor substrate IRS1 1993 receptors proposed for EGF-receptor discovered - Cancer cells and virally activation - SH3 domains bind short transformed cells 1983 1989 Pro-rich peptides produce growth factors - Establishment of Ras/MAPK - v-sis encodes for PDGF-B - Crk SH2 domain binds to signaling pathway chain tyrosine phosphorylated proteins - Establishment of JAK-Stat - Tyrosine phosphatase cloned signaling pathway - Phosphorylated tail of EGF - PH domains identified receptor binds GAP and PLCγ - PH domain mutated in Btk SH2 domains leading to immunodeficiency - FGF receptor cloned 1997 - Structure of FGFR kinase domain in complex with inhibitor determined - Docking protein FRS2 discovered - Inactive Src structure 2002 determined - Structure of EGF/EGFR 2006 ectodomain dimeric complex 2010 1995 determined - Allosteric activation of EGFR - Structure of monomeric ErbB3 kinase revealed by asymmetric - Structural basis for negative - PH domains bind to ectodomain determined kinase domain interactions cooperativity of EGF binding phosphoinositides - Sutent approved by the FDA to EGFR revealed - PTB domain binds pTyr - Klotho isoforms cooperates with - RTK selectivity is mediated - The PI3KAkt signaling 2001 FGFRs to mediate the action of by a secondary SH2 domain- pathway established - Gleevec approved by FDA endocrine FGFs binding site 2000 2010 1999 2007 1996 2004 - Structure of FGFR kinase - Structure of FGF/FGFR - Structure of SCF/KIT - Activating EGFR mutants domain determined ectodomain dimeric ectodomain dimeric are sensitive to gefitinib complex determined complex determined - Cbl negatively 2008 regulates EGFR by 2003 - Heterogeneity of EGFR ubiquitination - Structure of monomeric binding arises from EGFR ectodomain negative cooperativity of determined dimerization system Figure 1. A time line of key findings during the history of RTKs, with emphasis on findings and discoveries that produced the conceptual framework in the development of the RTK field and its application for cancer therapy. References for the key findings are also presented in the text (Lee et al. 1985; Libermann et al. 1985; Margolis et al. 1990; Bottaro et al. 1991; Bae et al. 2009). 2 Cite this article as Cold Spring Harb Perspect Biol 2014;6:a008912 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press History of Receptor Tyrosine Kinases produce and use their own growth factors and/ role of the cell-surface receptor being to act as a or use cellular processes that in normal cells are “carrier” that delivers them directly to these tar- regulated by exogenously supplied growth fac- gets. An alternative hypothesis was that insulin tors; both predictions were subsequently con- or EGF activates their cognate receptors at the firmed. Avariety of new polypeptide growth fac- cell surface, which in turn stimulate the produc- tors that stimulate cell proliferation by binding tion of an intracellular second messenger mole- to receptors at the cell surface were subsequently cule analogous to cAMP in signaling by the G- discovered. Those include a growth factor iso- protein-activating b-adrenergic receptor. In- lated from human platelets designated platelet- deed, several potential second messengers that derived growth factor (PDGF; Antoniades et al. are generated in cells on stimulation with insulin 1979; Heldin et al. 1979), a growth factor isolat- or other growth factors were proposed before ed from bovine brain designated fibroblast (and even after) it became clear that insulin re- growth factor (FGF; Gospodarowicz et al. ceptor, EGFR, and other RTKs are endowed with 1978), a growth factor isolated from rat platelets intrinsic tyrosine kinase activity (Larner et al. that stimulates the proliferation of mature hepa- 1979; Das 1980; Saltiel and Cuatrecasas 1986). tocytes, designated
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