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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

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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).

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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 hepatocyte growth factor A demonstration that anti-insulin receptor (HGF; Nakamura et al. 1986). In addition to antibodies from the serum of certain diabetic EGF,another growth factor that binds selectively patients could mimic cellular responses of insu- to cells expressing EGFR was isolated from vi- lin (Flier et al. 1977; Van Obberghen et al. 1979) rally and chemically transformed cells, suggest- provided the first conclusive answer to the ing that this growth factor—designated trans- question of whether the biological activity of forming growth factor a—may play a role in growth factors is mediated directly or indirectly oncogenesis by an autocrine mechanism (Rob- through their membrane receptors. This exper- erts et al. 1980, 1982). This discovery provided iment ruled out the possibility that insulin re- further support to the earlier finding that trans- ceptor functions as a passive carrier that delivers formation by murine and feline sarcoma viruses insulin to an intracellular target to induce cellu- selectively interferes with EGF binding to EGFR lar responses. Studies showing that intact, biva- in transformed cells (Todaro et al. 1976). To- lent antibodies against the insulin receptor can gether with many other studies published since activate its signaling, whereas monovalent Fab the 1980s, this work showed that growth factors fragments of the same antibodies cannot further and their receptors play numerous important argued that ligand-induced receptor dimeriza- roles during development and in many normal tion or stimulation of a particular arrangement cellular processes as well as in pathologies such between two receptor molecules in a dimer can as cancer, diabetes, atherosclerosis, severe bone activate the insulin receptor (Kahn et al. 1978). disorders, and tumor angiogenesis. A similar conclusion was reached using cer- Visualization of dynamic cellular redistribu- tain monoclonal antibodies that bind to the ex- tion of ligand/receptor complexes, and rapid tracellular region of EGFR and block ligand receptor-mediated internalization of growth binding (Schreiber et al. 1981). Whereas intact factors such as insulin or EGF,ledto the proposal antibodies were able to mimic EGF in stimulat- that cell-surface receptors for these ligands may ing avariety of EGF-like responses including cell play a passive role in delivering them to intracel- proliferation, monovalent Fab fragments of the lular compartments in which internalized EGF same monoclonal EGFR antibodies failed to do or insulin molecules exert their actions (Vigneri so—and acted instead as EGFR antagonists et al. 1978; Podlecki et al. 1986; Jiang and Schin- (Schreiber et al. 1981, 1983). These experiments dler 1990). In other words, according to this provided strong evidence both that EGFR plays a hypothesis, the biological signals induced by in- crucial role in mediating EGF-induced cellular sulin or EGF were thought to be mediated by responses and that EGFR is activated by ligand- binding of the ligandsthemselvesto intracellular induced receptor dimerization (Schreiber 1981, target(s) in the cytoplasm or nucleus, with the 1983).

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J. Schlessinger

GROWTH FACTOR RECEPTORS ARE growth factor receptor (PDGFR) or insulin re- ENDOWED WITH PROTEIN TYROSINE ceptor, respectively, in the stimulated cells sug- KINASE ACTIVITY gested that insulin receptor and PDGFR possess tyrosine kinase activity (Ek et al. 1982; Kasuga Valuable insights into the mode of action of et al. 1982). Becasue tyrosine phosphorylation growth factors and their receptors were ob- was seen with the oncogenic proteins Src and tained from advancement in molecular charac- Abl, as well as with growth factor-stimulated terization of the modes of action of retroviral surface receptors such as EGFR, PDGFR, and oncogenic proteins. An interesting convergence insulin receptor strongly suggested that it plays of two different fields of biomedical research an important role in normally regulated cell was taking place in the late seventies and early proliferation as well as in aberrantly stimulated eighties, leading to the elucidation of mecha- proliferation of cancer cells, and that these pro- nisms responsible for transformation of cells teins all activate a common enzymatic activity by a family of retroviral oncogenes. These stud- (i.e., protein tyrosine kinases). ies led to the discovery of a common enzymatic Biochemical analysis of EGFR expressed in activity used in controlling cell growth, and re- A-431 or other cultured cells showed that EGFR vealed the key features of how growth factors is a glycosylated, transmembrane receptor of stimulate cell proliferation by binding to their molecular weight of 170 kDa, which is com- cell-surface receptors. prised of a large extracellular ligand binding re- The first key insight was provided by molec- gion connected via a transmembrane domain to ular characterization of the oncogene product, a cytoplasmic region that becomes phosphory- Src, from Rous sarcoma virus (Brugge and Erik- lated on tyrosines on stimulation with EGF. son 1977). It was reported that Src is a protein However, in the absence of any direct informa- kinase that phosphorylates primarily threonine tion about the primary structure of EGFR and residues (Collett and Erikson 1978). Subse- other members of the growth factor receptor quent experiments performed using lysates of family, it was not obvious whether the tyrosine EGF-stimulated human epidermoid carcinoma kinase activity is encoded within the same gene cells A431, which express very high levels of that endows EGFR with specific EGF binding EGFR (more than two million copies) on their or whether the observed tyrosine kinase activity cell surface, similarly revealed EGF stimulation arises from a closely associated protein encoded of threonine phosphorylation (Carpenter et al. by a separate gene. Other EGFR-associated ac- 1978). A more thorough examination by Hun- tivities were also reported. For example, a topo- ter and Sefton (1980) of the phosphorylation isomerase activity associated with purified induced by the Src oncogenic product revealed EGFR—which leads to ATP-stimulated DNA- that this was a unique kinase that phosphory- nicking activity—was proposed to represent an lates tyrosines rather than serines or threonines. intrinsic activity of EGFR or to become associ- Subsequent studies revealed that EGFR stimu- ated with EGFR during membrane solubiliza- lation also leads to phosphorylation of tyro- tion (Miskimins et al. 1983; Mroczkowski et al. sines, the mistake arising because phosphoty- 1984; Basu et al. 1985). Further characterization rosine (P-Tyr) and phosphothreonine (P-Thr) of EGFR isolated from A-431 cells showed that comigrate in the electrophoresis experiments the isolated EGFR can be recognized specifically performed at pH 1.9 (Ushiro and Cohen by antibodies generated against certain synthet- 1980). It was also shown that the Abelson Leu- ic peptides from the tyrosine kinase domain of kemia virus protein, Abl, promotes tyrosine Src, suggesting that the cytoplasmic region of phosphorylation (Witte et al. 1980). Moreover, EGFR may indeed contain a tyrosine kinase do- subsequent studies showed that treatment of main (Lax et al. 1984). cultured cells with PDGF or insulin-induced With the partial sequencing of peptides de- tyrosine phosphorylation. The fact that this rived from human EGFR revealing a link be- was dependent on expression of platelet derived tween the retroviral oncogene v-erbB and the

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History of Receptor Tyrosine Kinases

EGFR (Downward et al. 1984), and subsequent as RTKs. A wealth of information accumulated cloning of human EGFR cDNA that allowed the during the late 1970s and early 1980s demon- receptor’s amino acid sequence to be deduced strating that insulin or EGF stimulation leads (Ullrich et al. 1984), the molecular nature of to the clustering of insulin receptor or EGFR, EGFR became clear. These findings showed respectively, on the cell surface. Moreover, the that the EGFR contains a large extracellular li- cellular responses of EGF or insulin could gand binding domain (620 aa), a single trans- be stimulated by bivalent, but not by monova- membrane helix, and a large (540 aa) cyto- lent, receptor antibodies. Biochemical studies plasmic region that contains a tyrosine kinase showed that, before ligand activation, EGFR is domain. The tyrosine kinase domain is preced- expressed on the cell surface as a monomer, ed by a short juxtamembrane region of 30 aa whereas insulin receptor and the closely related that was later shown to play an important reg- IGF1 receptor are both expressed on the cell ulatory role, and is followed by a long carboxy- surface as preexisting disulfide linked dimers. terminal tail of 230 aa that contains most of It was also shown that the homodimeric struc- the tyrosine autophosphorylation sites (Down- ture of the inactive insulin receptor is essential ward et al. 1984; Ullrich et al. 1984). This mo- for the negative cooperativity observed in bind- lecular characterization also showed that the ing of insulin to its receptor (De Meyts 2008). v-erbB oncogene of the avian erthryoblastosis The establishment of the primary structures virus encodes a truncated avian EGFR that has of EGFR, PDGFR, and other RTKs showed that lost most of the extracellular ligand-binding re- the ligand-binding region of RTKs is separated gion as well as part of the carboxy-terminal tail from the cytoplasmic region by a single trans- containing tyrosine autophosphorylation sites. membrane helix. The identification of the Importantly, these studies revealed that the structural topology of EGFR and other mono- retroviral oncogene v-erbB induces cell trans- meric RTKs triggered an intense debate about formation by encoding an EGF-independent how ligand binding to an extracellular region variant of avian EGFR that has constitutively transfers a stimulatory cue across the cell mem- stimulated tyrosine kinase activity (Downward brane to stimulate tyrosine kinase activity in the et al. 1984; Ullrich et al. 1984; Kris et al. 1985). cytoplasmic region. This finding added to earlier studies that The two main mechanisms proposed for had revealed the first link between a retroviral how EGF binding to the extracellular region oncogene and a growth factor, namely, the dem- stimulates the tyrosine kinase activity in the onstration that the v-sis oncogene of simian sar- EGFR cytoplasmic region are presented in Fig- coma virus encodes the growth factor PDGF ure 1. The top panel in Fig. 2A depicts an “in- (Doolittle et al. 1983; Waterfield et al 1983). It tramolecular mechanism” in which EGF induc- was concluded that this virus had captured/ es a conformational change in the extracellular transduced the gene for a growth factor and region that is transmitted via the transmem- the product of the retroviral v-sis oncogene in- brane helix to activate the tyrosine kinase do- duces cell transformation by autocrine stimula- main in the cytoplasmic region. Accordingly, tion of PDGFRs expressed on the surface of the ligand-stimulated EGFR monomers transmit a same cells that secrete PDGF molecules (Doo- structural change across the single transmem- little et al. 1983; Waterfield et al. 1983). brane helix to activate the catalytic tyrosine kinase activity in cis and to mediate autophos- phorylation on multiple tyrosine residues. RTKs ARE ACTIVATED BY In other words, according to this model, both DIMERIZATION tyrosine kinase activation and autophosphor- As previously mentioned, the central role of ylation are mediated by an intramolecular receptor dimerization as a mechanism of acti- process (Bertics et al. 1985; Gill et al. 1987; Ko- vation of insulin receptor and EGFR was re- land and Cerione 1988; Northwood and Davis vealed before these two receptors were defined 1988).

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J. Schlessinger

A

B

Figure 2. Two contrasting views during the early days for how EGF binding to the extracellular region of EGFR stimulates the tyrosine kinase domain in the cytoplasm. (A) An “intramolecular” mechanism. Ligand-stimu- lated EGFR monomers transmit a conformational change through the transmembrane helix to activate the tyrosine kinase domain and mediate autophosphorylation by an intramolecular process. (B) An “intermolec- ular” mechanism. Ligand binding stimulates lateral contacts between a pair of EGFR molecules, resulting in EGFR dimerization mediated by interactions between extracellular regions, transmembrane domains, and cytoplasmic regions resulting in stimulation of tyrosine kinase activity and autophosphorylation by an inter- molecular process.

The bottom panel (Fig. 2B) depicts an isting insulin receptor dimer provides an exam- “intermolecular mechanism” for information ple in which ligand-induced dimerization per se transfer from the extracellular region to the cy- is not required for signaling. Insulin activates its toplasmic region, in which ligand binding in- receptor by promoting an allosteric transition duces lateral contacts between two receptors, within this preexisting receptor homodimer resulting in their dimerization, which is respon- (De Meyts 2008)—effectively stabilizing an ac- sible for stimulation of the tyrosine kinase ac- tive configuration of the dimeric receptor. An tivity and for autophosphorylation. According- allosteric/dimerization model for ligand-in- ly, both tyrosine kinase activation (Kashles et al. duced stimulation of EGFR is shown in Figure 1991) and tyrosine autophosphorylation are 3A, which is modified from the original model mediated in trans by an intermolecular process described by Yarden and Schlessinger (1987). (Honegger et al. 1989). The model proposes that monomeric receptors It is now well established that dimerization are in equilibrium with receptor dimers. It is or formation of larger oligomeric structures is proposed that the monomeric receptor shows required for activation of most, if not all, RTKs weak ligand-binding affinity and low or inactive (Lemmon and Schlessinger 2010). Numerous tyrosine kinase activity. The dimeric receptor cellular studies using advanced microscopic shows high ligand-binding affinity and elevated methods, as well as biochemical studies in cells tyrosine kinase activity. KD is the dissociation and in vitro have shown that EGF promotes di- constant for EGF binding to EGFR monomers merization of its receptor. However, the preex- and KR is the dissociation constant for EGF

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History of Receptor Tyrosine Kinases

A Kagg1

KD KR

Kagg2

B Inactive dimer Active dimer

Inactive monomers PP

PPPP Ligand-bound Active dimer active dimer

Figure 3. Models for ligand stimulation of RTK dimerization and activation. The scheme presented in (A)is based on data from Yarden and Schlessinger (1987) with minor modifications. The scheme presented in (B) is based on data presented in Schlessinger et al. (2000). This is a generalized allosteric/dimerization model for RTK activation that applies equally to EGFR and insulin receptor. Full details are presented in the body of the article.

binding to EGFR dimers. Kagg1 is the dimeriza- it binds ligand argues that dimerization—al- tion constant of EGFR monomers and Kagg2 is though required—is not necessarily sufficient the dimerization constant for EGFR dimers. It for receptor activation. Instead, it is likely that 2 was previously shown that Kagg1/Kagg2 ¼ KR/ “inactive” dimers are in equilibrium with “ac- 2 KD (Yarden and Schlessinger 1987). According tive” dimers as shown in Figure 3B. Ligand bind- to this model, the enhanced binding affinity of ing to an active dimer will stabilize it, whereas EGF to dimeric EGFR confers the dimeric state binding to an inactive dimer will induce a con- on EGFR resulting in stimulated tyrosine kinase formational change to promote activation (as activity. For EGFR and many other RTKs, before seen for insulin and its receptor). In both cases, ligand-binding monomers predominate—al- this ligand binding will pull the equilibrium to though this depends on the receptor expression the right in Figure 3—constituting ligand-in- level (Chung et al. 2010). For the insulin recep- duced dimerization. The original model from tor, this equilibrium is shifted almost entirely to 1987 assumed that the ligand-binding sites in dimereven in the absence of ligand. The fact that the dimeric EGFR do not interact. More recent the dimeric insulin receptor is not active until studies suggest that interactions between the

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J. Schlessinger

ligand-binding sites are responsible for the ble activated (2:2:2) FGFR-containing complex negative cooperativity and for the curvilinear (Schlessinger et al. 2000). Scatchard plots of EGF binding to EGFR in liv- Structural analysis of the free or ligand-oc- ing cells (Alvarado et al. 2010; Pike 2012)—as is cupied extracellular regions of EGFR, KIT, also well documented for the insulin receptor FGFR, and other RTKs as well as the analysis of (De Meyts 2008). A generalized allosteric/dime- the catalytic kinase domains of the insulin re- rization model can be drawn for RTK activation ceptor, EGFR, and other RTKs provided valu- that applies equally to EGFR and insulin recep- able insights into the allosteric nature of the in- tor described by Schlessinger (2000) is presented teractions that regulate them (Lemmon and in Figure 3B. Schlessinger 2010). Examples include asymmet- Although ligand stimulation of receptor by ric interactions between the tyrosine kinase specific dimerization is a universal mechanism domains of EGFR that provide a direct alloste- for RTK activation, different ligands use differ- ric mechanism for tyrosine kinase activation ent strategies for stabilizing structural changes (Zhang et al. 2006), asymmetric arrangement that are required for stimulation of tyrosine ki- and partial ligand occupation of dimers of the nase activity. Drosophila EGFR extracellular region, which provide a mechanism for negative cooperativity of EGF binding to EGFR (Alvarado et al. 2010; Dimeric RTKs Ligands Pike 2012), asymmetric contacts between the The ligands of all type-III RTKs, including tyrosine kinase domains of FGFR providing a PDGFR, KIT, and other members of the family, potential mechanism for the ordered tyrosine are dimeric molecules. Structural studies have autophosphorylation of FGFR (Bae et al. shown that binding of stem cell factor to the 2010), and structural insights into the role ligand-binding region in the ectodomain effec- played by juxtamembrane domain of EGFR in tively “crosslinks” two KIT molecules, resulting the control of tyrosine kinase activity (Jura et al. in the formation of homotypic contacts between 2009; Red Brewer et al. 2009). the membrane proximal regions of the ectodo- mains of receptor pairs (Yuzawa et al. 2007). HOW TYROSINE PHOSPHORYLATION ACTIVATES CELLULAR SIGNALING Ligand-Induced Receptor-Mediated PATHWAYS Dimerization The mid 1990s saw a dramatic convergence of Dimerization of EGFR and other members of experimental insights obtained from biochemi- the family is entirely mediated by receptor-me- cal, structural, and genetic studies that provided diated interactions. Ligand binding to individ- a molecular view of both how tyrosine phos- ual protomers induces a conformational change phorylation regulates RTK activity and how ty- in the extracellular region of EGFR that exposes rosine phosphorylation activates multiple sig- a dimerization site that is occluded in the ab- naling pathways to relay information from the sence of ligand by autoinhibitory intramolecu- cell membrane to the nucleus and other intra- lar interactions (Burgess et al. 2003). cellular compartments. Intriguingly, regulation of the tyrosine kinases themselves (through au- tophosphorylation) is one of the most im- Ligand and Accessory Molecule-Mediated portant roles of tyrosine phosphorylation of Dimerization RTKs and nonreceptor protein tyrosine kinases FGF acts in concert with heparin sulfate proteo- (Hubbard et al. 1994). All tyrosine kinases con- glycans to crosslink two fibroblast growth factor tain 1–3 tyrosines in the activation loop of receptors (FGFRs). Direct contacts between the catalytic core that, in most known cases, FGF and heparin, FGF and FGFR, and hepa- are the first tyrosine(s) to be phosphorylated rin with FGFR mediate the formation of a sta- following stimulation. Enzymatic analyses and

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History of Receptor Tyrosine Kinases

structural studies have shown that autophos- SH2 domain followed by two SH3 domains phorylation of these tyrosines maintains the ac- (Matsuda et al. 1990). It was shown that in vi- tivation loop in an “open” configuration per- rally transformed cells, Crk forms complexes mitting ATP binding to the nucleotide binding with several tyrosine-phosphorylated proteins site and (by stabilizing the “active” conforma- (Matsuda et al. 1990). Importantly, it was shown tion of the kinase) enabling transfer of the g that the SH2 domains of Crk bind directly to P- phosphate to tyrosines of bound substrate mol- Tyr-containing proteins and peptides, suggest- ecules (Hubbard et al. 1994; Lemmon and ing that the biological role of SH2 domain of Schlessinger 2010). signaling molecules is to recognize P-Tyr sites Inspection of the pattern of tyrosine phos- within specific sequence contexts (Mayer and phorylated cellular proteins following growth Hanafusa 1990; Matsuda et al. 1991; Pawson factor stimulation showed that, in most cases, 2004; Waksman and Kuriyan 2004). the most strongly phosphorylated protein is the On the basis of these and other studies that receptor of the stimulating growth factor. Most are described in several review articles (Pawson of the tyrosines that become autophosphory- 1995, 2004; Lemmon and Schlessinger 2010), it lated on RTKs are located in noncatalytic was established that a variety of SH2 domain- regions of the cytoplasmic domain, such as the containing signaling molecules, including en- juxtamembrane region (e.g., PDGFR and KIT), zymes such as PLCg, the tyrosine phosphatase the kinase insert region (e.g., FGFR and KIT), or Shp2, and the GTPase-activating protein GAP the carboxy-terminal tail. EGFR and other for Ras, form complexes with activated EGFR members of the ErbB family of RTKs become and other RTKs by binding to specific P-Tyr sites phosphorylated on multiple tyrosines located in the receptor molecule. Complex formation primarily in the carboxy-terminal tail of the re- with an activated RTK leads to efficient tyrosine ceptor. One of the first clues as to how this au- phosphorylation of PLCg, a step necessary for tophosphorylation serves to propagate RTK sig- stimulation of its phospholipase activity (Lem- naling came from the finding that one substrate mon and Schlessinger 2010). Additional pro- molecule that becomes phosphorylated in re- teins that form complexes with activated recep- sponse to EGF stimulation, phospholipase Cg tors include the small adaptor proteins Crk, (PLCg), also forms a stable complex with the Grb2, and Nck. These adapter proteins are com- activated receptor (Margolis et al. 1989; Meisen- posed entirely of SH2 and SH3 domains with helder et al. 1989). It was subsequently shown architectures of SH2-SH3-SH3 for Crk, SH3- that complex formation between activated SH2-SH3 for Grb2, and SH3-SH3-SH3-SH2 EGFR and PLCg is mediated by the Src homol- for Nck (Pawson 1995). Biochemical studies to- ogy 2 (SH2) domain of PLCg that binds directly gether with genetic screening in Drosophila and to a P-Tyr site in the carboxy-terminal tail of Nematodes have shown that Grb2 provides a EGFR (Margolis et al. 1990). The SH2 domain link between RTKs and the Ras/Map kinase is a small protein module of 100 aa, initially (MAPK) signaling pathway. Grb2 uses its SH2 discovered as regulatory region in Src kinases domain for binding to the phosphorylated tail responsible for maintaining tyrosine kinase ac- of activated EGFR and its two SH3 domains for tivity of Src kinases in an inactive configuration recruitment of the nucleotide exchange factor, by mediating intramolecular autoinhibitory in- SOS, to provide a direct link between EGFR teractions (Sadowski et al. 1986). Src, PLCg, and stimulation and the GTPase Ras (Pawson 2004; many signaling proteins contain an additional Lemmon and Schlessinger 2010). Activated Ras small protein module designated the SH3 (for in turn stimulates a kinase cascade, ultimately Src homology 3) domain, which binds specifi- leading to MAP kinase stimulation. Another ex- cally to short, proline-rich regions in target pro- ample is the regulatory subunit, p85, of PI-3 teins (Pawson 1995, 2004). Interestingly, a viral kinase, which uses its SH2 domain to form a oncogenic protein, designated Crk, does not complex with activated RTKs leading to PI-3K contain any enzymatic activity, but only a single activation (Pawson 1995, 2004). It was con-

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cluded that RTKs function not only as enzymes Bae JH, Boggon TJ, Tome´ F,Mandiyan V,Lax I, Schlessinger but also as platforms for recruitment of a va- J. 2010. Asymmetric receptor contact is required for ty- rosine autophosphorylation of fibroblast growth factor riety of signaling molecules that stimulate the receptor in living cells. Proc Natl Acad Sci 107: 2866– activities of a variety of intracellular signaling 2871. pathways including the RAS/MAPK signaling Bae JH, Lew ED, Yuzawa S, Tome´ F, Lax I, Schlessinger J. pathway, the PI-3K/Akt signaling pathway, 2009. The selectivity of receptor tyrosine kinase signaling is controlled by a secondary SH2 domain binding site. and the Jak2/STAT signaling pathways, among Cell 138: 514–524. others. Basu M, Frick K, Sen-Majumdar A, Scher CD, Das M. 1985. Another mechanism for recruitment and ac- EGF receptor-associated DNA-nicking activity is due to a tivation of signaling molecules by activated Mr-100,000 dissociable protein. Nature 316: 640–641. RTKs involves docking proteins such as insulin Bertics PJ, WeberW,Cochet C, Gill CN. 1985. Regulation of receptor substrate 1 (IRS1) and other memberof the epidermal growth factor by phosphorylation. J Cell Biochem 29: 195–208. the IRS family and FGF receptor substrate 2 Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, (FRS2). It was shown that docking proteins Vande Woude GF, Aaronson SA. 1991. Identification of bind via their PTB domains to the insulin recep- the hepatocyte growth factor receptor as the c-met proto- tor or FGFRs, respectively, and become phos- oncogene product. Science 251: 802–804. phorylated on numerous tyrosine. The P-Tyr à Boucher J, Kleinridders A, Kahn CR. 2014. Insulin receptor signaling in normal and insulin-resistant states. Cold sites of docking proteins provide a platform Spring Harb Perspect Biol doi: 10.1101/cshperspect. for the recruitment and activation of an addi- a009191. tional complement of signaling molecules that Brugge JS, Erikson RL. 1977. Identification of a transforma- bind to the P-Tyr sites of the docking proteins tion-specific antigen induced by an avian sarcoma virus. via their own SH2 domains (Lemmon and Nature 269: 346–348. Burgess AW, Cho HS, Eigenbrot C, Ferguson KM, Garrett Schlessinger 2010), and are responsible for me- TP, Leahy DJ, Lemmon MA, Sliwkowski MX, Ward CW, diating many of the known insulin-induced cel- Yokoyama S. 2003. An open-and-shut case? Recent in- lular responses (see Boucher et al. 2014). The sights into the activation of EGF/ErbB receptors. Mol Cell 12: 541–542. signaling pathways that are initiated at the cell 125 membrane by activated RTKs and their specifi- Carpenter G, Cohen S. 1976. I-labeled human epidermal growth factor. Binding, internalization, and degradation cally associated docking proteins are responsible in human fibroblasts. J Cell Biol 71: 159–171. for regulating many critical cellular processes Carpenter G, King L Jr, Cohen S. 1978. Epidermal growth essential for cell proliferation, cell differentia- factor stimulates phosphorylation in membrane prepa- tion, cell survival, and metabolism during de- rations in vitro. Nature 276: 409–410. velopment and normal homeostasis. Dysfunc- Carpenter G, Lembach KJ, Morrison MM, Cohen S. 1975. Characterization of the binding of 125I-labeled epidermal tion in the activation or regulation of RTK growth factor to human fibroblasts. J Biol Chem 250: stimulated signaling networks plays a critical 4297–4304. role in a variety of human pathologies. Carpentier JL, Gorden P,Barazzone P,Freychet P,Le Cam A, Orci L. 1979. Intracellular localization of 125I-labeled in- sulin in hepatocytes from intact rat liver. Proc Natl Acad ACKNOWLEDGMENTS Sci 76: 2803–2807. Chung I, Akita R, Vandlen R, Toomre D, Schlessinger J, I thank Mark Lemmon for his excellent sugges- Mellman I. 2010. Spatial control of EGF receptor activa- tions for this work. tion by reversible dimerization on living cells. Nature 464: 783–787. Cohen S. 1962. Isolation of a mouse submaxillary gland REFERENCES protein accelerating incisor eruption and eyelid opening ÃReference is also in this collection. in the new-born animal. J Biol Chem 237: 1555–1562. Collett MS, Erikson RL. 1978. Protein kinase activity asso- Alvarado D, Klein DE, Lemmon MA. 2010. Structural basis ciated with the avian sarcoma virus src gene product. Proc for the negative cooperativity in growth factor binding to Natl Acad Sci 75: 2021–2024. an EGF receptor. Cell 142: 568–579. Das M. 1980. Mitogenic hormone-induced intracellular Antoniades HN, Scher CD, Stiles CD. 1979. Purification of message: Assay and partial characterization of an activa- human platelet-derived growth factor. Proc Natl Acad Sci tor of DNA replication induced by epidermal growth 76: 1809–1813. factor. Proc Natl Acad Sci 77: 112–116.

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History of Receptor Tyrosine Kinases

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History of Receptor Tyrosine Kinases

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Receptor Tyrosine Kinases: Legacy of the First Two Decades

Joseph Schlessinger

Cold Spring Harb Perspect Biol 2014; doi: 10.1101/cshperspect.a008912

Subject Collection Signaling by Receptor Tyrosine Kinases

CSF-1 Receptor Signaling in Myeloid Cells The Genesis of Tyrosine Phosphorylation E. Richard Stanley and Violeta Chitu Tony Hunter The EGFR Family: Not So Prototypical Receptor Structure-Function Relationships of ErbB RTKs in Tyrosine Kinases the Plasma Membrane of Living Cells Mark A. Lemmon, Joseph Schlessinger and Donna J. Arndt-Jovin, Michelle G. Botelho and Kathryn M. Ferguson Thomas M. Jovin Tie2 and Eph Receptor Tyrosine Kinase Activation Receptor Tyrosine Kinases: Legacy of the First and Signaling Two Decades William A. Barton, Annamarie C. Dalton, Tom C.M. Joseph Schlessinger Seegar, et al. The Spatiotemporal Organization of ErbB The Role of Ryk and Ror Receptor Tyrosine Receptors: Insights from Microscopy Kinases in Wnt Signal Transduction Christopher C. Valley, Keith A. Lidke and Diane S. Jennifer Green, Roel Nusse and Renée van Lidke Amerongen Insulin Receptor Signaling in Normal and Regulation of Receptor Tyrosine Kinase Ligand Insulin-Resistant States Processing Jérémie Boucher, André Kleinridders and C. Colin Adrain and Matthew Freeman Ronald Kahn Central Role of RET in Thyroid Cancer Molecular Mechanisms of SH2- and Massimo Santoro and Francesca Carlomagno PTB-Domain-Containing Proteins in Receptor Tyrosine Kinase Signaling Melany J. Wagner, Melissa M. Stacey, Bernard A. Liu, et al. Receptor Tyrosine Kinase-Mediated Angiogenesis Eph Receptor Signaling and Ephrins Michael Jeltsch, Veli-Matti Leppänen, Pipsa Erika M. Lisabeth, Giulia Falivelli and Elena B. Saharinen, et al. Pasquale Biology of the TAM Receptors Effects of Membrane Trafficking on Signaling by Greg Lemke Receptor Tyrosine Kinases Marta Miaczynska For additional articles in this collection, see http://cshperspectives.cshlp.org/cgi/collection/

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