Neuron,

Vol. 9, 383-391,

September,

1992, Copyright

0 1992 by Cell Press

Growth Factor Signaling by Receptor Tyrosine Kinases J. Schlesinger* and A. Ullricht *New York University Medical Center Department of Pharmacology New York, New York 10816 +Max-Planck lnstitut fur Biochemie Martinsried Germany

Cell-ceil communication is crucial for the develop ment and subsequent survival of multicellular organisms. A great variety of cellular signals induced by secreted polypeptides regulate growth, differentiation, and metabolic homeostasis of individual cell types in higher organisms. During the last decade, many peptide growth factors and cytokines have been discovered and the cell surface receptors that mediate their biological functions have been characterized. One large group of growth and differentiation factors act by binding to and activating surface receptors with intrinsic protein tyrosine kinase activity. While some receptors, such as insulin-like growth factor 1 (IGF-I), epidermal growth factor (EGF), and fibroblast growth factor (FGF), are widely expressed and therefore appear to play a fundamental role in tissue regeneration and maintenance, other receptors exhibit cell typespecific expression. For example, the colony-stimulating factor 1 (CSF-1) receptor fulfills specific signaling functions in macrophage differentiation and osteoclast activation. Similarly, receptors for nerve growth factor (NGF) and other neurotrophic factors are crucial for differentiation and survival of cells in the nervous system. All receptor tyrosine kinases are composed of three major domains; an extracellular domain connected via a single membrane-spanning domain to a cytoplasmic domain (reviewed in Ullrich and Schlessinger, 1998). The extracellular domain is responsible for ligand binding and transmission of the biological signal to the cytoplasmic domain, whose role is to transmit the biological signal to intracellular target proteins. The cytoplasmic domain contains, in addition to the catalytic protein tyrosine kinase, distinct regulatory sequences with tyrosine, serine, and threonine phosphorylation sites. The tyrosine kinase activity of growth factor receptors is critical for the signal transduction pathways required for mitogenesis, transformation, and cell differentiation (reviewed in Ullrich and Schlessinger, 1998). Signaling pathways initiated by tyrosine phosphorylation lead to various nuclear events, which eventually elicit dramatically different biological responses. The predominant biological activity of certain receptor tyrosine kinases is to stimulate cell growth and proliferation, while other receptor tyrosine kinases arrest growth and promote differentiation. Moreover, the same receptor tyrosine kinase can inhibit or stimulate cell proliferation when

Review

expressed in different cellular environments. For example, NGF and other neurotrophic factors elicit neuronal survival and differentiation upon binding to and activating different members of the trk family of receptor tyrosine kinases (Cordon-Cardo, 1991; Glass et al., 1991; Kaplan et al., 1991a, 1991b; Klein et al., 1990, 1991a, 1991b; Loeb et al., 1991; Squint0 et al., 1991; Soppet et al., 1991). However, NGF stimulation of the trk receptor tyrosine kinase induces proliferation of transfected fibroblasts (Glass et al., 1991; Barbacid et al., 1991). In fact, trk was originally isolated as an oncogene in a tumorigenicity assay of NIH 3T3 cells transfected with human tumor DNA (reviewed in Barbacid et al., 1991). FGF is also able to induce dramaticallydifferent responses by interactingwith receptors in fibroblasts or in neuronal cells. Basic and acidic FGFs were originally discovered as potent mitogens of various types of mammalian cells, including murine and human fibroblasts. However, treatment of primary neuronal cells or rat pheochromocy-toma (PC12) cells (Greene and Tischler, 1976) with acidic or basic FGF leads to growth arrest and differentiation into a sympathetic neuronal phenotype (Togari et al., 1985; Wagner, 1991). Yet, stimulation of PC12 cells with EGF, which activates the EGF receptor tyrosine kinase, leads to stimulation of cell growth and proliferation. It appears, therefore, that the stimulatory or inhibitory effects on cell proliferation are determined by the properties of the receptor tyrosine kinase and the cellular environment in which it is expressed. Several serine/threonine kinases have been shown to be activated in response to growth factor stimulation of receptor tyrosine kinases. EGF, platelet-derived growth factor (PDGF), NGF, and other growth factors stimulate the MAPlERK kinases. Activation of MAP kinase requires both tyrosine and serinel threonine phosphorylation. This kinase is therefore thought to be located at an important regulatory junction in the action of receptor tyrosine kinases. Other serine/threonine kinases activated in response to growth factor stimulation include c-raf, protein kinase C, and ribosomal S6 protein kinase. The ordering of these kinases within a signaling cascade is not yet clear. Surprisingly, the various biological effects of EGF and NGF on PC12 cells appear to be similar. Both EGF and NGF stimulate the activity of phosphatidylinositol (PI) hydrolysis, MAP kinase, S6 kinase, and ~21” activity (reviewed in Chao, 1992). Furthermore, NGF and EGF induce the expression of a similar repertoireof early response genes. Hence, detailed analysis of the early effects induced by EGF or NGF did not provide any clue that could explain the dramatically different biological effects of these two factors on PC12 cells. So far, there is no indication of any early response that heralds and distinguishes the mitogenic effect of EGF over the dramatic effects of NGF on cell differentiation.

In this review we summarize studies that provide new insights into the mechanisms underlying the activation of receptor tyrosine kinases. We also describe recent results and raise hypotheses concerning the molecular mechanisms that determine the selectivity of signaling pathways activated by receptor tyrosine kinases. Dimerization as a Mechanism Receptor Activation

for

Following ligand binding, all known growth factor receptors appear to undergo receptor dimerization (Schlessinger, 1988; Ullrich and Schlessinger, 1990). However, different growth factors or hormones are able to induce receptor dimerization by a variety of mechanisms. Growth factors such as PDGF are dimerit molecules, and the dimerization of their receptors is thought to be mediated by ligand-induced bridging of two PDGF receptors (Hart et al., 1988; Heldin et al., 1988,1989). The two known forms of PDGF (A and B types) are able to form AA, BB homodimers and AB heterodimers. Similarly, the two forms of the PDGF receptor are displayed on the cell surface as aa Quantitaand BB homodimers and up heterodimers. tive binding studies indicate that the various dimeric forms of the PDCF receptor exhibit differential binding specificity for the various dimeric forms of the PDGF ligands. Hence, receptor dimerization can expand the repertoire of receptor ligand interactions and may even extend the diversity of signals generated. A different mechanism is utilized by growth hormones. A single growth hormone molecule is able to bind two growth hormone receptor molecules and induce receptor dimerization by bridging two receptor molecules (Cunningham et al., 1991). The insulin receptor, on the other hand, is displayed on the cell surface as a disulfide-bridged homodimer of a and B insulin receptor subunits. Insulin appears to activate its surface receptor by inducing an allosteric transition within a preexisting dimeric structure (reviewed in Ullrich and Schlessinger, 1990). Growth factorinduced receptor dimerization was first demonstrated for the EGF receptor. Yet the mechanism of EGF receptordimerization is poorly understood, since one EGF molecule binds toa single EGF receptor molecule (Weber et al., 1984), indicating that EGF-induced receptor dimerization is probably mediated by a conformational change (Greenfield et al., 1989) in the extracellular domain that stabilizes the interactions between two occupied receptor molecules (Lax et al., 1991; Hurwitz et al., 1991). All in all, receptor dimerization appears to be a general property of all growth factor receptors. Figure 1 summarizes the various steps involved in the activation of receptor tyrosine kinases. The first step is ligand-induced receptor dimerization, which is responsible for the activation of the intrinsic protein

6

LIGAND

l

INACTIVE MONOMERS

ACTIVE DIMERS

TRANS AUTOPHOSPHORVLATION

TVROSINE DEPHOSPHORVLATION

SUBSTRATE PHOSPHORVLATION

Figure

1. Allosteric

Dimerization

Model

for Receptor

Activation

Ligand binding induces receptor dimerization, which activation of the intrinsic protein tyrosine kinase activity singer, 1988). Receptor dimerization is also responsible phosphorylation, which is mediated by an intermolecular cess. Tyrosine autophosphorylation on multiple sites specific binding sites for target proteins, which bind to vated receptor with their SH2 domains.

leads to (Schlesfor autoprocreates the acti-

tyrosine kinase activity. Kinetic analysis of EGF receptor autophosphorylation and substrate phosphorylation revealed a second-order reaction with respect to EGF receptor concentration, indicating that dimerization is essential for kinase activation (reviewed in Schlessinger, 1988; Ullrich and Schlessinger, 1990; Canals, 1992). These results are in accord with dominant negative experiments showing that coexpression of wild type and defective EGF receptor mutants results in formation of inactive heterodimers and suppression of tyrosine phosphorylation and biological activity mediated by the normal EGF receptors (Honegger et al., 1990; Kashles et al., 1991). Moreover, the oncogenie capacity of the EGF receptor can be suppressed by the dominant negative action of various signalingdefective EGF receptor mutants (Redemann et al., 1992). Subsequently, dominant negative suppression of PDGF receptor signaling by coexpression of a defective PDGF receptor mutant has also been described (Ueno et al., 1991). Furthermore, FGF-induced ventral mesoderm in early amphibian embryogenesis is suppressed by expression of a signaling-defective

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FGF receptor deletion mutant in theembryo (Amayaet al., 1991). These experiments provide genetic support for receptor dimerization as the mechanism for receptor activation. A reasonable hypothesis, therefore, is that receptor dimerization represents a universal mechanism for the activation of transmembrane signaling of receptors with a single transmembrane domain connecting the extracellular ligand-binding domain to the cytoplasmic domain. If this is true, then receptor dimerization could be the mechanism underlying the activation of many types of surface receptors in addition to receptor tyrosine kinases (Ullrich and Schlessinger, 1990). These would include receptorswith serinejthreonine kinase activity, such as the TGFB receptor (Lin et al., 1992), receptors with guanylyl cyclase activity, such as the natriuretic peptide receptor (Lowe et al., 1989), and receptors with tyrosine phosphatase activity (Fischer et al., 1991). Cytokine and hormone receptors with a relatively shortcytoplasmic domain, which appear to mediate their biological functions by activating cytoplasmic tyrosine kinases, are also among this group. In addition to its role in kinase activation, receptor dimerization sets the stage for autophosphorylation, which is mediated by an intermolecular mechanism (Honegger et al., 1989, 1990; Lammers et al., 1990). Moreover, intermolecular phosphorylation may also occur between two related receptors, such as the transphosphorylation of c-erbB2 by the EGF receptor (King et al., 1988) and the transphosphorylation between distinct FGF receptors (Bellot et al., 1991). Tyrosine autophosphorylation is crucial for normal receptor signaling. The tyrosine-autophosphorylated regions in growth factor receptors represent specific binding sites for cytoplasmic target proteins involved in transmission of the biological signal. Tyrosine phosphorylation and functional regulation of the activity of these intracellular target proteins leads to cellular pleiotropic responses essential for mitogenesis or differentiation. SHZContaining Proteins Interact Growth Factor Receptors

with Activated

Thetyrosine-phosphorylated regions in growth factor receptors function as high affinity binding sites for cellular proteins such as phospholipase C-y (PLC-y) and the GTPase-activating protein (GAP) of ras (Sub et al., 1988; Trahey et al., 1988; Vogel et al., 1988; Stahl et al., 1988; Meisenhelder et al., 1989; Margolis et al., 1989, 199Oa, 199Ob; Wahl et al., 1989; Burgess et al., 1990). These and other signaling proteins are able to recognize specifically different growth factor receptors, and the association between these proteins is strictly dependent on phosphorylation of the receptor molecules on tyrosine residues (Margolis et al., 199Oa). Theassociation between thetyrosine-phosphorylated regions in growth factor receptors and the signaling

proteins is mediated byaconserved region of approximately 100 amino acids, termed src homology 2 domains (SH2) (Koch et al., 1991; Heldin, 1991; Margolis, 1992). SH2 domains represent recognition motifs for specific tyrosine-phosphorylated peptide sequences. SH2 domains are usually accompanied by another conserved domain of 50 amino acids, termed the SH3 domain, whose function is still poorly understood. An expression-cloning method, referred to as cloning of receptor targets, was developed for the cloning of proteins that bind to the activated EGF receptor. With this procedure, the tyrosine-phosphorylated carboxy-terminal tail of the EGF receptor is used as a probe for screening of expression libraries (Skolnik et al., 1991; Margolis et al., 1992a). By using this method and other more conventional approaches, numerous SH2-containing proteins have been identified. Figure 2 depicts a summary of SHZ-containing proteins that play a role in signaling pathways activated by receptor tyrosine kinases and cytoplasmic tyrosine kinases. On the basis of their primary structures, it is possible to divide these proteins into two main classes. Type I defines proteins that contain, in addition to the SH2 (and usually also SH3) domains, distinct enzymatic activities, such as phospholipase (PLC-y), tyrosine kinase (p~60~-~“), and putative GDP-GTP exchange functions (vav) (Katzav et al., 1989; Bustelo et al., 1992; Margolis et al., 1992b; Adams et al., 1992). The SH2 domains of this class of signaling molecules directly mediate their interaction with tyrosine-phosphorylated receptors and other tyrosine-phosphorylated proteins. Such SHZ-containing proteins are thought to be able to exert their distinct enzymatic activities and transmit a biological signal upon tyrosine phosphorylation or by virtue of their interaction with neighboring target proteins. PLC-y can be considered a prototype for this class of signaling proteins. The binding of EGF, PDGF, or FGF to their specific cell surface receptors leads to stimulation of tyrosine autophosphorylation. This creates specific binding sites for the SH2 domains of PLC-T specifically at three tyrosine autophosphorylation sites in the carboxyterminal tail of the EGF receptor fY992, Y1068, and Y1173) and at one site in the carboxy-terminal tail of the FGF receptor fY766). The binding of the SH2 domains is crucial for efficient tyrosine phosphorylation of PLC-y-it increases the affinity (decreasing the Michaelis constant) for tyrosine phosphorylation by the EGF receptor (Rotin et al., 1992b). Elimination of Y766 of the FGF receptor prevents binding of PLC-y to the FGF receptor, inhibits tyrosine phosphorylation of PLC-y, and abolishes FGF-induced PI hydrolysis (Mohammadi et al.,1992). In addition, elimination of PLC-y Y783 prevents PDGF-induced stimulation of PI hydrolysis, indicating that phosphorylation on Y783 is essential for stimulation of PLC activity (Kim et al., 1991). These results indicate that the association between PLC-y and activated growth factor receptors is essential for tyrosine phosphorylation of PLC-11 and that

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386

Figure 2. Signaling SH2 Domains

I Tyrosine

src

Kinase

m

phospholipasa PLCq

phorpholipaaa

C

1

SHS 810

GTPase Activating GAP

Tyrosine

phosphatase

PTPlC GDPlGTP

exchanger

Zinc Finger

C

Proteins

Containing

(1) Proteins that contain distinct enzymatic activities in addition to SH2 domains. SK, tyrosine kinase activity; PLC-T, phospholipase C activity; GAP, CTPase-activating protein of ras; PTPIC, putative tyrosine phosphatase activity(Shen et al., 1991); vav, putative GDP-CTP exchange factor activity. (II) SHZ-containing proteins that serve as adaptors or regulatory subunits of downstream signaling proteins. GRBl/pBS, regulatory subunit of PIZkinase; c-crk, cellular homolog of the v-crk oncogene product; rick, a protein phosphorylated by the EGF and PDGF receptors; GRBZsem-5 protein involved in EGF receptor signal transducation in human and nematode, respectively.

vav

II

ORBlIp

sla’ SHS

c-crk

rick

tyrosine phosphorylation activates PLC-?I, leading to the generation of diacylglycerol and inositol trisphosphate, two second messengers responsible for activation of protein kinase C and release of calcium from internal stores, respectively. The second class of SHZ-containing proteins includes c-crk, rick, and GRB?/semS (Mayer et al., 1988; Lehmann et al., 1990; Clark et al., 1992; Lowenstein et al., 1992). These proteins are composed of virtually only SH2 and SH3 domains (Figure 2). Type II SH2containing proteins are thought to function as adaptors or regulatory components of specific catalytic subunits. For example, the PI3-kinase-associated p85 is the regulatory subunit of pIlO, which is likely to functionasthecatalyticsubunitof PI3-kinase(Carpenter et al., 1990; Skolnik et al., 1991; Escobedo et al., 1991; Otsu et al., 1991; Hu et al., 1992; McGlade et al., 1992). Another example of a type II protein is the oncogene product of the avian CT10 virus, p47gag*“. The v-crk protein is associated with tyrosine-phosphorylated proteins, and its expression leads to enhancement of total cellular tyrosine phosphorylation. Moreover, mutations in the SH2 domain of v-crk decrease tyrosine phosphorylation and abolish virusinduced transformation (Mayer et al., 1988; Mayer and

Hanafusa, 1990). CR62 protein is another member of the type II SH2-containing proteins. GRB2 contains one SH2 domain flanked by two SH3 domains (Lowenstein et al., 1992). Like other signaling proteins, GRB2 associates with the EGF and PDGF receptors in a ligand-dependent manner, both in vitro and in living cells. The association between GRB2 and growth factor receptors is mediated by the SH2 domain. The association is strictly dependent upon receptor tyrosine autophosphorylation and involves a direct interaction between CRB2 and the tyrosine-phosphorylated receptors. GRB2 is the human homologof sem-5, a Caenorhabditis elegans signal transduction protein (Lowenstein et al., 1992; Clark et al., 1992). sem-5 and two other genes, let-23 (EGF receptor like) and let-60 (ras like), lie along the signal transduction pathway that controls vulva1 induction in C. elegans (Aroian et al., 1990; Clark et al., 1992; Horvitz and Sternberg, 1991). The structural similarity between GRB2 and sem-5 is also reflected in the analogous functions of these two proteins. We have recently shown in collaboration with M. Stern that GRB2 is able to rescue sem-5 mutations in C. elegans and that sem5 protein is able to bind specifically to the tyrosine-autophosphorylated human EGF receptor (unpublished data). On the basis

Review: 387

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Nematode let-23 sem-5

1

let-60

Human .- - --c

Figure

GRB2

e----c

ras

3. AModelfortheRoleofGRB2andsem5in

PDGFR

FGFR

EGF-receptor

+---)

Vulva1 Induction

EGFR

Cell proliferation rassignaling

In response to ECF stimulation, CRB2 (or sem-5) binds to the EGF receptor (or let-23) via its SH2 domain (Clark et al., 1992; Lowenstein et al., 1992). ras (or let-SO) acts downstream, leading to either ceil proliferation or vulva1 induction. CRB2 (or sem-5) may control growth factor-induced ras (let-60) signaling, stimulating a GDP-GTP exchange factor, by inhibiting a ras GTPase activity or both.

of the genetics of C. elegans and the properties of GRB2, it is likely that sem-5 will bind tyrosinephosphorylated let-23 via its SH2 domain. Since mutations that cause loss of function in let-60 cause a phenotype similar to that resulting from mutations in either let-23 and sem5 and since activated ras can rescue let-23 and sem5 mutations, it is reasonable to assume that Iet-Wras functions downstream from the EGF receptor and GRB2 and that GRB2 is involved in regulation of ras activity (Figure 3). Moreover, intact GRB2 protein and H-ras cooperate to stimulate DNA synthesis when microinjected into rat fibroblasts (Lowenstein et al., 1992). Hence, GRB2 and its as yet unidentified associated protein(s) may control growth factor-induced ras signaling by stimulating the activity of a GDP-CTP exchange factor, by inhibiting a ras GTPase activity, or by both mechanisms. Genetic analysis of eye development in Drosophila provides a parallel picture showing a link between receptor tyrosine kinases and ras signaling. A GDPGTP exchange factor encoded by son of sevenless regulates ras function in a manner that is dependent upon the sevenless receptor tyrosine kinase (Simon et al., 1991). Different Signaling Proteins Bind to Distinct Phosphorylated Regions in Growth Factor Receptors The identification of tyrosine autophosphorylation sites in growth factor receptors combined with functional analysis of mutated receptors in transfected cells has enabled the assignment of specific binding sites for different signaling proteins (Kazlauskas and Cooper, 1989, 1990; Kazlauskas et al., 1992; Margolis et al., 199Ob; Rotin et al., 1992a; Mohammadi et al., 1991, 1992; Shurtleff et al., 1990; Van der Geer et al., 1991; Kashishian et al., 1992). Short synthetic tyrosine-

Figure ylated

4. Different Signaling Proteins Bind to Distinct Regions in Growth Factor Receptors

Phosphor-

The carboxy-terminal tail of the EGF receptor contains five tyrosine autophosphorylation sites, including three binding sites for PLC-T c/992, YlOSB, and Y1173) and one binding site for GRB2 (YIOEB). The PDCF receptor contains five tyrosine autophosphorylation sites: two binding sites for pB5 fY74Oand Y751), one binding site for ras GAP C/771), and two binding sites for PLC-T (YlOO!T and Y1021). The FCF receptor contains three tyrosine autophosphorylation sites, but only one site is characterized fY766) as the binding site for PLC-T.

phosphorylated peptides corresponding to identified tyrosine autophosphorylation sites are able to inhibit the binding of certain SHZ-containing proteins to the tyrosine-phosphorylated PDGF receptor (Fantl et al., 1992). Specificity of interaction was also determined by direct binding experiments between recombinant SH2 domains and tyrosine-phosphorylated peptides corresponding to autophosphorylation sites of different growth factor receptors. For example, PLC-y SH2 domains bind with high affinity(dissociation constant I-IO nM) to tyrosine-phosphorylated sites on the EGF and FGF receptors. However, the affinity of GAP SH2 and p85 SH2 domains for the tyrosine-phosphorylated FGF receptor peptide is 208 to 500-fold lower Welder et al., submitted). Similarly, p85 SH2 domains bind tyrosine-phosphorylated peptides from the PDGF receptor with high affinity and do not bind tyrosinephosphorylated peptides from the EGF or FGF receptors. Specificity of interaction was demonstrated for phosphopeptide sequences and for SH2 domains. Figure 4 illustrates the assignment of various binding sites for signaling molecules on the EGF, PDGF, and FGF receptors. It was shown that the SH2 domains of p85 bind to a YMXM motif found in the PDGF receptor, CSF-1 receptor, middle T antigen, and a major insulin receptor substrate, IRS-1 (Cantley et al., 1991; Sun et al., 1991; Backer et al., 1992). High affinity binding sites for the SH2 domain of PLC-y were identified in the carboxy-terminal tail of the FGF receptor (Mohammadi et al., 1991) and the EGF receptor (Rotin et al., 1992a). Comparison of the sequences in this region reveals a common motif, VILXXXXEYL, found around Y766 of the FGF receptor and around Y992, Y1068, and Y1173 of the EGF receptor. However, this sequence motif does not exist around Y1148 and Y1086 of the

EGF receptor, two tyrosine-phosphorylated regions that do not bind the SH2 domain of PLC-y (Rotin et al., 1992a). The EGF receptor contains three binding sites for the SH2 domain of PLC-y and one binding site for CR62 at Y1068 (Batzer et al., unpublished data) (Figure 4). The kinase insert region of the PDGF receptor contains two binding sites for p85 at Y740 and Y751 and one site for rasGAP at Y771 (Kazlauskas and Cooper, 1990; Kashishian et al., 1992; Kazlauskas et al., 1992; Fantl et al., 1992). The carboxy-terminal tail of the PDGF receptor contains two binding sites for PLC-y at Y1009and Y1021 (C. Heldin, personal communication) (Figure 4). Finally, the FCF receptor contains three tyrosine phosphorylation sites, but as yet only one site has been identified at Y766 (Figure 4) as a binding site for PLC--y (Mohammadi et al., 1991, 1992). A variation on the same theme is represented by the insulin receptor. Activation of the insulin receptor kinase leads to tyrosine phosphorylation of YMXM motifs on IRS-1 (Sun et al., 1991). The phosphorylated YMXM motifs on IRS-1 create specific binding sites for the SH2 domain of Pl3-kinase-associated ~85, leading to stimulation of PIIkinase activity (Backer et al., 1992). It therefore appears that the various tyrosine phosphorylation sites on IRS-1 function as binding sites for different signaling proteins, which are recruited upon tyrosine phosphorylation of IRS-1 and are responsible for transmitting the broad range of activities stimulated by insulin. Do SH2 Domains Control Signaling Pathways?

the Specificity

of Receptor

The interaction between SHZ-containing proteins and tyrosine-phosphorylated regions in growth factor receptors and tyrosine-phosphorylated proteins such as IRS-1 and middle-T antigen (Cantley et al., 1991; Sun et al., 1991; Backer et al., 1992) may provide a simple paradigm for explaining specificity of signaling pathways for receptor tyrosine kinases. According to this model, autophosphorylation of growth factor receptors on multiple sites generates specific binding sites for a variety of proteins containing intracellular SH2 domains. Tyrosine autophosphorylation or interaction with tyrosine-phosphorylated regions modulates the functions of these proteins. According to this hypothesis, the activity of a given receptor tyrosine kinase equals the sum of the activities of the signaling proteins that interact with its tyrosine-phosphorylated form. Elimination of tyrosine autophosphorylation sites should therefore prevent the activation of specific signaling pathways. Consistent with this hypothesis is the finding that FGF-induced PI hydrolysis is totally eliminated by a point mutation of the FGF receptor at Y766, which prevents the association with and tyrosine phosphorylation of PLC-?I (Mohammadi et al., 1992). Similarly, elimination of Y740 and Y7Sl of the PDGF receptor abolishes the binding of p85 and activation of PI3-kinase activity (Kashishian et al., 1992). Deletion of carboxy-terminal PDGF receptor se-

123456

123789 Figure 5. A Model for Control of Specificity of Receptor Signaling Pathways by Interaction with SHZ-Containing Proteins According to this model, different cell types express, in addition to common target proteins responsible for general cellular functions (target proteins 1,2, and 3), a set of cell type-specific, SH2containing proteins (target proteins 4,5, and 6 in cell type I and target proteins 7, 8, and 9 in cell type II). These proteins are responsible for determining specialized cellular responses after interaction with the same ligand-activated receptor tyrosine kinase.

quences results in the loss of PLC-y functions (Seedorf et al., 1992). We also postulate that different cell types express, in addition to common target proteins required for general cellular functions, a cell type-specific set of SHZcontaining signaling proteins responsible for determining specialized cellular responses. Most SHZ-containing proteins currently known, such as PLC-~, ~85, rasGAP, and GRB2/semd (Figure 2), are widely expressed. However, certain proteins containing SH2 domains have a restricted distribution. For example, the proto-oncogene vav (Figure 2) is exclusively expressed in hematopoietic cell lineages (Katzav et al., 1989; Adams et al., 1992). The SH2containing tyrosine phosphatase PTPIC (Shen et al., 1991) also has a limited distribution. A recently cloned SHZ-containing protein denoted GRB7 is expressed only in the kidney and liver (Margolis et al., 1992b). It appears, therefore, that these tissue-specific SH2containing proteins have a more specialized role in receptor tyrosine kinase-mediated signal transmission pathways.Accordingtothisview,Iigand-induced

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stimulation of the NGF receptor will activate distinct signaling pathways in PC12 cells, as compared with fibroblasts, because these two cell types contain, in addition to common target proteins, a different repertoire of cell type-specific SHZ-containing proteins (Figure 5). These yet to be discovered tissue-specific target proteins will interact with the tyrosine-autophosphorylated NGF receptors and, upon activation, transmit signals leading, on one hand, to mitogenesis in fibroblasts and, on the other hand, to growth arrest and differentiation in PC12 cells (Figure 5). To understand these processes fully, many additional questions need to be addressed. For example, most SHZcontaining proteins also contain SH3 domains, which clearly play an important role in signal transmission (Clark et al., 1992; Lowenstein et al., 1992). In addition, certain proteins devoid of SH2 domains are tyrosine phosphorylated by receptor tyrosine kinases. Moreover, the role of serinelthreonine phosphorylation of growth factor receptors is poorly characterized, and most kinases that are responsible for these processes are still unknown. Nevertheless, it is already clear that the SH2 motif and its capacity to interact with receptortyrosine kinases playacrucial role in the cascade of events leading to cell growth and differentiation. Acknowledgments This work HFSPO.

was supported

by grants

from

SUCEN,

Inc., and from

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is the specific-

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Growth factor signaling by receptor tyrosine kinases.

Neuron, Vol. 9, 383-391, September, 1992, Copyright 0 1992 by Cell Press Growth Factor Signaling by Receptor Tyrosine Kinases J. Schlesinger* and...
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