Review IIIIIIII II
J BiomedSci 1994;1:65-82
Departmentof Microbiology, The Mount SinaiSchoolof Medicine, NewYork, N.Y., USA
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KeyWords Growth factor Ligand Oncogenesis Phosphotyrosine Receptor
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Oncogenes, Protein Tyrosine Kinases, and Signal Transduction
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Abstract Many oncogenes encode protein tyrosine kinases (PTKs). Oncogenic mutations of these genes invariably result in constitutive activation of these PTKs. Autophosphorylation of the PTKs and tyrosine phosphorylation of their cellular substrates are essential events for transmission of the mitogenic signal into cells. The recent discovery of the characteristic amino acid sequences, of the s r c homology domains 2 and 3 (SH2 and SH3), and extensive studies on proteins containing the SH2 and SH3 domains have revealed that protein tyrosine-phosphorylation of PTKs provides phosphotyrosine sites for SH2 binding and allows extracellular signals to be relayed into the nucleus through a chain of protein-protein interactions mediated by the SH2 and SH3 domains. Studies on oncogenes, PTKs and SH2/SH3-containing proteins have made a tremendous contribution to our understanding of the mechanisms for the control of cell growth, oncogenesis, and signal transduction. This review is intended to provide an outline of the most recent progress in the study of signal transduction by PTKs. ~oe.t...o.
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Cellular proliferation and differentiation are normally regulated by growth factors through transmembrane receptors with intrinsic protein tyrosine kinase (PTK) activity. These receptor-type PTKs (RPTKs) have a common structural configuration. They all consist of an extracelllar ligand-binding domain, a single transmembrane (TM) domain, and an intracellular domain harboring the tyrosine kinase catalytic sequence [231]. The mitogenic signals of growth factors are transmitted into cells through their cognate receptors by activating their intrinsic PTK activity. The PTK activity is absolutely required for the signal transduction. Autophosphorylation of the activated receptors is usually the earliest response upon ligand stimulation. Ligand-induced oligomerization and intermolecu-
Received: June 2 , 1 9 9 3 Accepted: June25,1993
lar phosphorylation of RPTKs are considered to be a general mechanism for their activation [16, 204, 259]. Aside from activation of the catalytic PTK activity, little was known about the functional significance of autophosphor3dation until recently. Studies in the past several years on proteins containing s r c homology domains 2 and 3 (SH2 and SH3) have revealed that PTK autophosphorylation creates sites (phosphotyrosine motifs) for SH2 binding and thus initiates a chain of protein-protein interactions, fulfilling the signal transmission from extracellular growth factor to nucleus resulting in gene activation, DNA synthesis and cell proliferation or differentiation [25, 106].
Professor L u - H a i W a n g , P h D Box 1124, D e p a r t m e n t & M i c r o b i o l o g y T h e M o u n t Sinai School o f M e d i c i n e O n e G u s t a v e L. L e v y P l a c e N e w York, N Y 1 0 0 2 9 - 6 5 7 4 ( U S A )
Table 1, RPTK RPTK
Ligand
Oncogene Origin
Reference
EGFR
EGF
v-erbB
AEV-R(ES4) AEV-H
46 255
Neu
NDF
neu
neuroblastoma
79,243
HER3
?
erbB3
110
CSF- 1R
CSF- 1
v-f ms
FeSV
199
Kit
MGF
v-kit
FeSV
10
Ros
?
v-ros
ASV UR2
161,239
Met
HGF
met
osteosarcoma
35
NGFR
NGF NT-3
trk trkB trkC
colon carcinoma
136 105 114
FGFR
aFGF bFGF
f/g bek
196 175
Ret
?
ret
Sea
?
v-sea
PDGFR
PDGF
IR
insulin
human placenta
49,229
IGF-1R
IGF-1
human placenta
230
IRR
?
Flk-2
?
Ltk
?
Axl
?
223 AV S 13
214 249
208
axl
hematopoietic celt
143
lymphocyte, neuron
70
myeloid leukemia
166
AEV = Avian erythroblastosis virus; ASV = avian sarcoma virus; CSF = colony-stimulating factor; EGF = epidermal growth factor; FGF = fibroblast growth factor; FeSV = feline sarcoma virus; HGF = hepatocyte growth factor; IGF = insulin-like growth factor; IRR = insulin-receptor-relatedreceptor; NDF = Neu differentiation factor, NGF = nerve growth factor; NT = neurotrophin; MGF = mastocyte growth factor; PDGF = platelet-derived growth factor.
Regulation of Cell Growth by PTKs The importance of the control of cell growth by growth factors and the RPTKs is best exemplified by the finding that more than a dozen oncogenes have been documented to be altered cellular RPTKs (table 1). Structural and functional alterations of RPTKs invariably lead to subversion of the normal regulation of cell growth [1]. Truncation, internal deletion, point mutation and amplification of RPTK genes have been demonstrated to be common mechanisms for constitutive activation of RPTKs, which consequently promote cell transformation in vitro and oncogenicity in vivo [ 100, 244].
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The first example is the oncogenic counterpart of epidermal growth factor (EGF) receptor (EGFR), v-erbB, which was found to arise from c-erbB by truncation of almost the entire extracellular (EC) sequence and deletion of the C-terminal 34 amino acids (aa) including one major autophosphorylation site [46]. In addition, v-erbB harbors multiple point mutations in comparison with c-erbB. These structural changes render v-erbB constitutively active in its kinase activity and oncogenicity [ 138.209]. A second example of a truncated RPTK gene is v-fms transduced by the Gardner-Amstein strain of feline sarcoma virus. The concogene codes for a mutant version of colony-stimulating factor (CSF-1) receptor (CSF-1R; table 1). The v-fms oncoprotein is synthesized as a precursor fusion protein, gag-fms, which is subsequently cleaved and processed into gpl40 v'fms. In contrast to the v-erbB product, gp140 v-/ms appears to contain the complete ligand-binding domain of the CSF-1R [ 191]. The C-terminal 40 aa in the CSF- 1R have been replaced by 11 irrelevant residues in v-fms, including one t~a'osine residue. Similar ot the v-erbB product, this carboxyl terminal alteration may contribute to the increased tyrosine kinase activity and oncogenicity [199]. Another example of transduced RPTK genes comes from the discovery of v-ros, an oncogene originally found in avian sarcoma virus UR2 [7, 161,239, 240]. The protooncogene c-ros encodes a RPTK-like molecule [11, 28, 142, 160, 161 ]. Similar to v-erbB, v-ros has lost all but 7 aa of its EC domain and also has an altered carboxyl sequence [160, 162]. Like v-fins, v-ros is fused in-frame to the viral gag sequence. The resulting oncoprotein P68gag-r°s is constitutive in kinase activity and is highly transforming and oncogenic [84, 85]. Recent studies showed that c-ros was expressed in kidney and intestines and suggested that it may be important for both development and mature functions of those organs [29, 216,225]. A putative ligand for this RPTK-like molecule remains to be defined. Ros is most homologous to the sevenless protein of Drosophila melanogaster, the insulin receptor (IR) and the insulin-like growth factor-1 (IGF-1) receptor (IGF-1R) in their PTK domains [11, 28, 141,239]. Our studies on the human IR and IGFR and their mutants have also shown that these RPTKs indeed have cell-transforming and oncogenic potential [ 120, 121, 241 ]. The met oncogene was found in carcinogen-treated human osteosarcoma cells and seems to be activated by gene rearrangement such that a DNA segment from human chromosome 1 joins the 5" truncated c-met gene [35, 174, 224]. The fusion protein expressed from the met oncogene is a tyrosine-phosphorylated doublet of 60/65
Signal Transduction by Protein Tyrosine Kinases
kD as opposed to the 165- and 140-kD proteins encoded by the c-met proto-oncogene [224]. c-met proto-oncogene may be the prototype of a new class of tyrosine receptor with a heterodimeric subunit structure consisting of a 50kD c~subunit disulfide-linked to a 145-kD ~3subunit [64, 65]. The c-met proto-oncogene has been found to be amplified and overexpressed both in the GTL-16 gastric carcinoma cell line and in transfected NIH 3T3 cells [174]. Evidence for the transforming capability of the amplified c-met gene has been derived from transfection of NIH 3T3 cells with normal cellular DNA where cells from spontaneously occurring foci were found to contain a 4- to 8-fold amplification of c-met and at least a 20-tbld overexpression of a normal c-met transcript [36]. A recent finding showed that improper processing of Met precursor could cause oncogenic activation [152]. The Met precursor, which is normally cleaved into two subunits, is not processed in a protease-deficient tumor cell line LoVo. As a result, PTK activity of the uncleaved Met is constitutively activated. This may represent a new mechanism for constitutive activation of the RPTK. It was recently shown that the ligand for c-met turned out to be the hepatocyte growth factor (HGF) [I 8]. More extensive truncation and deletion are present in another retroviral oncogene, v-kit, which corresponds to c-kit transduced by the Hardy-Zuckerman-4 strain of feline sarcoma virus [10]. Compared with c-kit, v-kit has lost the entire EC and TM domains. The C-terminal 49 aa of c-kit were replaced by 5 unrelated residues in v-kit, again including the deletion of a potential autophosphorylation site [258]. Unlike the oncoprotein encoded by verbB, v-fins or v-ros, the v-kit gene product becomes associated with plasma membrane via the myristoylated gag sequence fused at the N-terminus of v-kit [10]. c-kit has been demonstrated to be the receptor for mastocyte growth factor (MGF) [37, 56, 83, 248]. The above examples suggest that truncation of the extracellular domains and/or deletion of the C-terminal tails remove negative regulatory elements, resulting in constitutive activation of erbB, fins, ros, and kit. A point mutation, rather than deletions or truncations, is found to be responsible for oncogenic activation of neu, a carcinogen-induced oncogene found in rat neuroblastoma [203]. A single point mutation of valine to glutamic acid in the TM sequence results in constitutive dimerization of the Neu receptor to give higher affinity for ligand binding [8]. There appear to be several ligands for the Neu receptor as demonstrated recently from cloned cDNAs coding for the putative ligands [79, 177, 243].
The oncogene trk was originally isolated from a human colon carcinoma cDNA library. This oncogene was generated by somatic rearrangement that resulted in fusion of the trk PTK sequence including the TM domain with a truncated nonmuscle tropomyosin molecule [ 136]. Protooncogene c-trk encodes a receptor molecule with a ligandbinding domain which is replaced in the oncogenic trkby a tropomyosin sequence [41, 137]. In this case, truncation and fusion to nonmuscle tropomyosin activated the oncogenic potential of c-trk, although other mechanisms like point mutation(s), deletion(s) and duplication(s) of the kinase domain could also activate its oncogenic potential [40]. It is now known that the c-trk product is a high-affinity nerve growth factor (NGF) receptor (NGFR) [104]. Several different forms of trk genes have been cloned recently and they code for a family of receptors with different specificities for a class of neurotrophic factors [105, 114]. The ret oncogene was activated by recombination between two unlinked segments of human DNA, probably during the transfection of NIH 3T3 cells with DNA isolated from a human T cell lymphoma [223]. This oncogene encodes a fusion protein consisting of an amino terminal part from an unknown protein sequence and the ret PTK including the TM domain. Similar to other RPTKs, and RPTK ocogenes ros, met, and trk, the regulatory EC domain of c-ret has been replaced by a novel sequence, presumably causing constitutive activation of the tyrosine kinase activity. As mentioned above, by truncation of the N-terminal EC domain mad fusion of the remaining j3 subunit of the human IR and IGFR to the retroviral gag sequence, the resulting Gag-IR and Gag-IGFR fusion receptors are constitutively activated and are capable of efficiently transforming cells in vitro and inducing tumors in vivo [120, 121,180, 241]. In both cases, the entire TM and cytoplasmic domains including the PTK regions are identical to their corresponding native receptors. Whether the activation of PTK activity is solely responsible for the oncogenic activation or whether there may be qualitative differences in signaling processes is unclear at present. Mutational studies on the C-termini of human IR and IGFR have shown that the C-terminus of IR has a negative modulatory effect on its mitogenic activity but has virtually no effect on the PTK activity [128]. By contrast, the C-terminus of IGFR has a positive effect on its transforming potential and PTK activity [ 122]. The oncogenic RPTKs and their normal counterparts have provided informative clues for understanding the mechanisms of activation of normal growth factor receptors. They also offer invaluable tools for studying signal
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Table2. Proteins containing SH2 and/or SH3 domains
ABPlp
actin binding
65
--SH3....
47
CDC25 Crk Csk FUS 1 GAP Grb2 Grb7 HS 1 ISGF-3c~ Myo 1B Myo 1L Nck PI3K p85
RAS pathway proto-oncogne src kinase yeast fusion GTPase activating PTK signaling EGFR signaling? ? IFN signaling actin binding actin binding PTK signaling PI3K subunit
? 35 50 ? 120 25 ? 75 84, 91, 113 ? ? ? 85
- -3H3- ---SH2-SH3-SH3---SH3-Sh2--PTK - -SH 3. . . . . . --SH2-SH3-SH2--GA --SH3-SH2-SH3--GH- -SH2- -LHL--SH3--SH3-SH2.... SH3-.... SH3---SH3-SH3-SH3-SH2--SH3-SH2-SH2--
21 144 197 228 227, 234 33, 123, 139, 170, 211 133 101 59 87 88 31, 115, 119, 148, 173 53, 171, 213
PLC-T PTP 1C
phospholipase phosphatase
140 67?
PLC-SH2-SH2-SH3-PLC - -SH2-SH2-PTPase--
218,220, 221 206
Shc
PTK signaling
46, 52, 66
--CH----SH2--
178
Spectrin Tensin Vav
membrane protein actin binding PTK signaling
? 90 95
. . . . . SH3-. . . . . SH2---SH3-SH2-SH3-
242 44 96
ZAP-70 p55
TCR signaling membrane protein
70 55
-SH2-SH2-PTK .... SH3--
27 194
p47 p67 p85
NADPH oxidase NADPH oxidase actin binding
47 67 85
--SH3--SH3----SH3--SH3--. . . . . SH3--
235 116 252
src-like kinase (e.g.fps, yes, abl) are not listed. For their structures, see references 76 and 195. ISGF3ct has three different components, p84/91 and p 113. Shc protein has three different species as indicated. Relative positions of SH2 and SH3 domains in the proteins are indicated, but the size of these proteins are not shown in scale. PTK = protein tyrosine kinase domain; GA = ras GTPase-activating domain; GH = GAP-homologous domain; HLH = helix-loop-helix domain; PLC = phospolipase C; PTPase = protein tyrosine phosphatase domain, CH = collagen homology domain, Myo = myosin; EGFR = eidermat growth factor receptor; IFN = interferon; PI3K = phosphatidylinositol-3 kinase; TCR = T cell receptor.
transduction in the process o f cell transtbrmation as well as their respective physiological functions. A separate group o f oncogenic PTKs, the nonreceptor PTKs, such as src, fps/fes, abl, yes, and so on, have also contributed tremendously to our understanding o f the mechanisms for cellular transformation and tumorigenesis [12, 86]. The accumulated evidence clearly suggests that protein tyrosine phosphorylation plays a crucial role in growth control and oncogenesis.
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Signal Transduction by PTKs Although molecular cloning o f genes encoding PTKs, including R P T K s and nonreceptor P T K s (e.g. the src family), has led to tremendous advances in understanding the structural alterations involved in constitutive activation o f tyrosine kinase activity and oncogenic potential [86, 231], not m u c h is known about how the activated P T K s achieve their ultimate biological effects, namely,
Signal Transduction by Protein Tyrosine Kinases
cell transformation and tumorigenicity. Since kinase activity is absolutely required for the function of PTK oncogenes, cellular substrates of the activated PTKs are logically the molecules that relay the mitogenic signals in the signaling pathways and lead to cell transformation. A great deal of effort has been directed to looking for tyrosine-phosphorylated cellular proteins using antiphosphotyrosine antibodies [57, 66, 90, 91, 190, 238]. A wide spectrum of cellular tyrosine phosphoproteins have been described [73, 86, 89]. However, their molecular identities are rarely known, let alone their functions. A new era began for the study of signal transduction when the noncatalytic regions of src-like kinases, src homology domains 2 and 3 (SH2 and SH3), were implicated in directing protein-protein interactions [94, 144, 200, 218]. Since then, more than 20 proteins have been reported to contain SH2 and/or SH3 domains (table 2). There is increasing evidence indicating that these noncatalytic domains are of primary importance in mediating cellular protein-protein interactions, and participate in signal transmission [for reviews see ref. 25, 176]. Recent progress in the study of signal transduction by PTKs is discussed below and schematized in figure 1.
SH2 and SH3 Domains Studies on cytoplasmic PTKs, such as src, fps/fes, abI, yes, fyn, Ick, fgr, have revealed, in addition to the conserved kinase domain, two other conserved noncatalytic regions [76, 144, 200]. One of the noncatalytic regions lying upstream of the P T K domain in src and fps was designated SH2 [200], the other was later designated SH3 [94, 106, 144, 218]. The importance of the SH2/SH3 domains was clearly recognized when Mayer et al. [144] discovered a unique retroviral oncogene, v-crk, which had no PTK catalytic sequences but only SH2 (B+C box) and SH3 (A box) domains. The SH2 domain consists of about 100 aa which have been found in nonreceptor PTKs and in many other seemingly unrelated proteins (table 2). Evidence has accumulated to clearly show that the SH2 domain binds to protein phosphotyrosine motifs and mediates the interacton between enzyme molecules and their substrates with high affinity and specificity [54, 146]. Mutations in the SH2 region have been shown to cause dramatic changes in biochemical properties and biological functions of these SH2-containing proteins (Src, Abl, and Crk) [ 147]. There are several well-conserved sequence motifs separated by more variable sequence elements inside the SH2 domain [ 106]. Crystal and solution structures of the SH2 domains have been recently reported, and they are characterized
DA
PK
Fig. 1. Schematic representation of PTK signalingpathways. The drawing represents a summary of what is discussed in the text. The question marks indicate that the signalingorientation is not yet well documented or that nothing is known about the downstream signal flow. The blank box represents the PTK domain. The black diamond represents the ligand. IP3 = Inositol-l,4,5-phosphate, DAG = diacylglycerol;PKC = protein kinase C.
by central [3-sheets flanked by two a-helices [ 17, 172, 238]. The central 13-sheets consists of five antiparallel small 13sheets. Binding of the SH2 domain to a phosphotyrosine peptide is suggested to be mediated by the N-terminal whelix, [3-sheet, and intervening loops [ 172, 238]. The highly conserved, positively charged residues (for instance, Arg155, Arg175 and Lys203 in v-src) form a small, shallow cleft and are important in correct positioning and binding of the phosphotyrosine site [238]. Arg155 is par-
69
ticularly important since it recognizes both the phosphate group and the aromatic ring of phosphotyrosine. Arg175 in the sequence FLVRES is strictly conserved among SH2 domains and is involved in specific hydrogen binding with two of the four phosphate oxygens of the phosphotyrosine. Dual SH2-domain-containing proteins might be able to facilitate the binding to dimeric targets, such as activated receptor PTK complex [ 172]. Most SH2-containing proteins are accompanied by a separate sequence motif of about 45 aa known as SH3, which was first described in v-crk and PLC-148 [144, 218]. Subsequently, the SH3 domain has been identified in many proteins that associate with the cytoskeleton and membrane [189] (table2). Several gene products have more than one SH3 domain, such as the NADPH oxidase subunits (p47, p67), Crk, Nck, Grb2 and Vav (table 2). Very little is known about the function of the SH3 domain. The association of SH3-containing proteins with the cytoskeleton and membrane implies a potential role for the domain in subcellular localization and morphogenesis [ 106]. Sequences of the partial cDNA clone of an SH3-binding protein, 3BP-1, show homology to GAPrelated proteins (rho-GAP), implying a functional association of SH3 proteins with GAP-like proteins and rasGTP-binding proteins [32]. A 10-aa proline-rich sequence, APTMPPPLPP, found in 3BP-1 was defined as an SH3-binding site [ 185]. Mutations in the SH3 domain of the v-src oncogene result in an altered morphology of the mutant-transfomled cells, suggesting that the SH3 domain might be involved in morphological transformation by v-src [236]. The crystal structure of the a-spectrin SH3 domain contains five antiparallel [3-sheets. The 9sheets form a smooth surface which is suggested to be a putative ligand-binding site [ 157]. Signaling Proteins for RPTKs Recently, several signaling proteins have been shown to be physically associated with activated receptor and nonreceptor PTKs. They include phospholipase (PL)C-? [ 132, 149, 237], ras-GTPase-activating protein (GAP) [2, 3, 92]. and phosphatidylinositol-3 kinase (PI3K) [ 13, 39]. GAP, PLC-y and PI3K all contain the SH2 domain. GAP is a 120-kD protein that directly interacts with cellular ras protein and enhances GTPase activity of ras, thereby acting as a negative regulator by returning ras from the active GTP-bound form to the inactive GDP-bound state [ 124, 227, 234]. Molecular cloning of GAP cDNAs shows that GAP contains two SH2 and one SH3 domains at its Nterminal region and a GTPase-activating domain at its Cterminus [227, 234]. GAP becomes tyrosine-phosphory-
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lated by and physically associated with activated EGFR and platelet-defived growth factor (PDGF) receptor (PDGFR) [3, 92, 98]. However, it is still not clear how increased tyrosine-phosphorylation of GAP affects its function. The SH2 domain of GAP has been shown to mediate binding of GAP to specific sequence motifs of the activated EGFR and PDGFR [54]. Tyrosine kinase also induces GAP to associate with two other tyrosine-phosphorylated proteins, p62 and p190 [153, 205, 250]. Surprisingly, p62 cDNA encodes a nucleic-acid-binding protein homologous to a putative hnRNP, GRP33 [250]. GAP binds to tyrosine-phosphorylated p62 through its SH2 domain, p 190 has been shown to be a multidomain protein, homologous to other GAP-activity-containing molecules, such as n-chimaerin, BCR (break point region for c-abl rearrangement in Philadelphia chromosome) oncoprotein, and rho-GAP [205]. p190 could be a potential link for signal transduction from membrane-associated tyrosine kinases to ras-GAP and then to the nucleus [72, 205]. The role of GAP domains in signal transduction becomes more intriguing when two clinically important genes, NF1 (neurofibromatosis type 1 susceptibility gene) and bcr, were shown to have GAP activity [253, 254]. GAP domains are highly conserved in yeast (IRA1, IRA2, CDC42 in Saccharomyces cerevisiae; gap t in Saccharomycespombe) and Drosophila (gap 1) [72]. It is worthwhile mentioning that GAP has a function other than down-regulating ras, namely coupling the K + channel to atrial muscarinic cholinergic receptor [135]. Thus, the role of GAP in signal transduction seems to be more complicated than simply down-regulating ras. PLC-y1 is one of several PLC isoforms which breaks down the phosphatidylinositol-4,5-bisphosphate (PIP2) to diacylglycerol (DAG) and inositol-l,4,5-trisphosphate (IP3) [129, 165, 187]. DAG stimulates protein kinase C (PKC) activity while IP3 increases release of intracellular calcium by binding to IP3 receptor on the endoplasmic reticulum (ER) membrane [9, 150]. The IP3 receptor has multiple transmembrane domains in its C-terminus and may regulate calcium channel opening [ 150]. The enzyme activity of PLC-y1 can be stimulated by PDGF, EGF, and fibroblast growth-factor (FGF) [111, 237, 249]. cDNA clones of PLC-y contain SH2 and SH3 domains [2t8, 220, 221]. PLC-y1 physically associates with activated PDGFR, EGFR and FGF receptor (FGFR) through its SH2 domain [131, 151]. Tyrosine phosphorylation of PLC-y1 is important for its activation and association with activated RPTKs [99, 149, 156, 163]. It seems that PLC-y1 is an important component for signaling by the PDGFR, EGFR, and FGFR. However, PLC-y1 may not SignalTransductionby ProteinTyrosine Kinases
be essential for the mitogenic activity of FGFR or PDGFR since mutants of those RPTKs that are unable to associate with or activate PLC-7 can still cause increased DNA synthesis in response to ligand stimulation [151, 179]. In addition, insulin and IGF-1 receptors can mediate mitogenic responses without phosphorylation of PLC-7, implying that PLC-7 is not essential for the mitogenicity of IR or IGFR [163]. The studies on FGFR association with PLC-7 also suggested that phosphatidylinositol (PI) turnover and calcium influx are not required for mitogenesis [ 151,236]. Two types of PI kinases have been reported. Type I PI3K phosphorylates the inositol ring of PI or PI derivatives (PI-4-P, PI-4,5-P2) at the Y position [245-247]. Type II PI-4 kinase (PI4K), phosphorylates the inositol ring at the 4' position [246, 247]. PI4K involved in the production of PI-4,5-P2 which is the precursor for the well-known second messengers DAG and IP3, as described above. The physiological role of the PI3K products (PI-3-P, PI-3,4-P2, and PI-3,4,5-P3) is not yet clear. The phospholipases that cleave, PI, PI-4-P, and PI-4,5-P2 do not hydrolyze any of the D-3 phosphoinositides, suggesting that the PI-3-P pathway is independent of the well-characterized PI-4-P pathway. Accumulated evidence indicates that PI3K is involved in mitogenic signaling of many oncogenes [60, 61, 93]. Purified PI3K is a heterodimer that consists of 85-kD (p85) and l l0-kD (pll0) polypeptides [26, 154]. Molecular cloning of cDNAs coding for PI3K shows that p85 has no catalytic sequences; instead, it contains SH2 and SH3 domains [53, 171, 213], whereas cDNA coding for p 110 has PI3K catalytic sequences and p85 is not required for the kinase activity ofp110 [78]. Increased PI3K activity is associated with both activated RPTKs like EGFR, PDGFR, IR, Ros, CSF-1R, and c-Kit [4, 51, 82,232], and nonreceptor PTKs, such as Src and Lyn [60, 256]. The association of PI3K with tyrosine phosphoproteins is through the SH2 domain [52, 126]. The structure of the p85 SH2 domain is reported to be similar to those ofv-src and c-abl [17, 172, 238]. Mutations of specific tyrosine-phosphorylation sites on PDGFR abolish its association with PI3K and obviate the growth-factor-induced mitogenesis [54]. PI3K activity is also complexed with p21 ras upon insulin or IGF-1 stimulation, suggesting a link between activated RPTKs (e.g. IR and IGFR) and the p21 ras pathway [212]. PI3K is able to associate with almost every activated RPTK and srclike PTK examined so far, but GAP is not detected in CSF-1R or the c-Kit complex, while PLC-7 fails to bind CSF-IR [25, 231,248]. Whether IR and IGFR bind GAP or PLC-7 remains to be elucidated. These lines of evi-
dence suggest that there are specific signal transduction pathways activated by different RPTKs, but also that these pathways overlap. Src and the related nonreceptor PTKs, such as Fyn and Yes, may directly participate in RPTK signal transduction, since Src, Fyn, and Yes PTKs are physically associated with, and are phosphorylated by the 13-PDGFR [I 12]. PDGF stimulation results in an increase in SRC kinase activity [68]. Src seems also to interplay with IGFR since in Src-transformed cells, tyrosine-phosporylation and kinase activity in IGFR are increased [t09]. However, the biological significance of this interaction remains unclear. Signaling Proteins for Nonreceptor PTKs Many proteins in Rous~sarcoma-virus-transformed cells become tyrosine-phosphorylated and are potential substrates ofpp60 src [73, 186]. A glycoprotein, gp130, was found to be a major substrate of pp60 ~c [74]. Phosphorylation of gpl30 seems to correlate with cell transformation [73, 74]. The molecular identity of gp130 remains unknown. It could be identical to the p130 described by others [186]. Another tyrosine-phosphorylated protein, pll0, is also physically associated with pp60 src [186]. p130 binds to the SH2 domain ofpp60 src, while p110 may associate with its SH3 domain [106]. A 95-kD protein tyrosine-phosporylated by v-src turns out to be the IGFR 13subunit, suggesting a possible interplay between the signaling pathways of the two PTKs [109]. Using cellular extracts containing enriched tyrosine-phosphorylated proteins from v-src-transformed cells as immunogens, Kanner et al. [91] obtained a panel of monoclonal antibodies specific for proteins tyrosine-phosphorylated by pp60 vsrc. Several cDNAs coding for the proteins have been molecularly cloned using the antibodies as screening probes. Among them, an 85-kD polypeptide is a ctyosketetal protein containing the SH3 domain, and is capable of binding to filamentous actin [252]. A 125-kD protein is a new cytoplasmic PTK associated with the focal adhesions in src-transformed cells [p125 F~;K,for focal adhesion kinase; ref. 202]. The tyrosine-phosphorylation of p125 FAK appears to correlate with cell transformation by src and the anchorage-independent growth of the transformed cells [69]. Two other proteins were also found in the src complex. One is the GAP protein, and the other, p62, is now known to be homologous to the hnRNP, GRP33, suggesting that these two proteins are also involved in src signal transduction [ 153, 250]. c-crk, originally found as an oncogene (v-crk) in avian sarcoma virus CT10 [144], codes for a 35-kD protein con-
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taining one SH2 and two SH3 domains without any recognizable catalytic sequence [184]. Compared with c-crk, verk is fused to the viral gag sequence in the N-terminus and has a large deletion of 100 aa in the C-terminus, including an SH3 domain present in the c-crk product [184]. Tyrosine-phosphorylation of cellular proteins of 62-, 70-, 120-, and 135- to 155-kD is markedly elevated in v-crk-transformed cells. The three major species of 70, 120, and 135-155 kD are specifically associated with the oncoprotein p47gag-crkin vitro [145]. Some cellular tyrosine kinase activities are coimmunoprecipitated with p47gag-erk. The p47 gag'crkcan also complex with p60 v-srcin vitro, and tyrosine-phosphorylation of p60 v-srcis required for their association [ 140]. It was recently shown that the SH2 domains of Crk and PLC-y can protect tyrosinephosphorylated EGFR from dephosphorylation in vitro by protein tyrosine phosphatases [ 188]. It may explain, at least to some extent, why Crk can enhance tyrosine-phosphorylation of cellular proteins. It has been known that phosphorylation of Tyr527 of pp60 src has an inhibitory effect on its tyrosine kinase activity [86]. A distinct cellular protein, Csk (C-terminal src kinase), is molecularly identified as a cytoplasmic tyrosine kinase specifically phosphorylating Tyr527 [159, 168, 197]. The c-src kinase activity is decreased after its phosphorylation by Csk which can also phosphorylate other src family members like p561Y~and p59fyn at tyrosine residues corresponding to the Tyr527 of pp60 c-src [167]. Coexpression of v-crk and c-src causes transformation of rat 3Y1 fibroblasts where c-src kinase activity was elevated. However, v-crk and c-src proteins did not seem to form a stable complex [197, 198]. Csk was shown to be capable of suppressing the transformation induced by coexpression of v-crk and c-src, but unable to reverse the transformed phenotype induced by v-src or c-src527F (Tyr527 mutated to phenylalanine). This study suggests that v-crk may activate c-src kinase in vivo by modulating the phosphorylating state of Tyr527. On the other hand, the oncogenic potential of pp60 c-src can be activated by overexpression of the phosphatase a (PTPasea) in rat embryo fibroblast, and the Tyr527 of c-src is specifically dephosphorylated by the PTPasea [260]. It seems that Crk, Csk and probably certain tyrosine phosphatases are involved in regulation of src PTK activity and its signal transduction. PI3K also appears to be involved in src signal transduction since it has been shown to associate with pp60 v-src [60, 61]. Their association is probably mediated by the SH2 domain of v-src and a tyrosine-phosphorylated sequence of the PI3K [60]. Moreover, the SH3 domain of
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v-src may also be involved in their association [236]. The association of PI3K activity with pp60 v-src is correlated
with its cell-transforming activity. However, several nontransforming src or kinase-inactive src mutants are also capable of associating with the PI3K activity. These results suggest that association of PI3K with src is not sufficient for transformation [60]. Accumulated evidence suggests that the PKC family is also involved in PTK signaling. PKC, a serine/threonine kinase, can be activated either by DAG, a catalytic product of activated PLC-7 as mentioned earlier, or by tumorpromoting phorbol esters, such as 12-O-tetradecanoylphorbol 13-acetate (TPA) [169]. Depletion of PKC by prolonged treatment of chicken embryo fibroblasts with phorbol esters blocked the induction of a transformationrelated gene, 9E3, by v-src and v-fps [217]. The same study also showed that the phosphorylation of a 67-kD PKC substrate was rapidly induced by activation of v-src and v-fps PTKs. By contrast, expression of another gene, Egr-1, induced by activation of v-src PTK, was not affected by either PKC depletion or PKC inhibition [ 182]. These studies indicate that v-src, and perhaps other nonreceptor PTKs (such as fps), may signal through both PKC-dependent and-independent pathways [75, 182, 217]. Ras, an Integration Point in Signaling Pathways o f R P T K s and src-Like P T K s
p21 ras, a well-characterized proto-oncogene with intrinsic GTPase activity, plays a critical role in signal transduction by activated tyrosine kinases [ 134]. Activation of the NGF, EGF, PDGF, insulin receptors and c-kit increases the proportion of the GTP-bound, activated form of p21 ras [63, 201 ]. Studies using a dominant inhibitory mutant of c-Ha-ms, Ha-ras(S17N), and microinjection studies using neutralizing anti-ras antibody have shown that the function of cellular Ras protein is essential for NGF, FGF, CSF-1, and v-src signal transduction [55, 71, 215, 251]. Cross-linking of the T cell receptors and stimulation of mast cells (R6X and MC-9) with interleukins (IL-3, IL-5), and granulocyte/macrophage-colonystimulating factor (GM-CSF) also cause accumulation of GTP-bound p21 ras [45, 48]. Although T cell receptors and those IL receptors have no tyrosine kinase activity, srclike kinases (Lck, Fyn, Lyn) and other tyrosine kinases like ZAP-70 have been shown to be recruited to the activated receptors and are thought to be involved in their signal transduction [27, 34, 77, 102]. Genetic studies on Drosophila eye development have shown that Ras protein is a key signaling element for two tyrosine kinases, sevenSignalTransductionby ProteinTyrosine Kinases
less (ros homolog) and Ellipse [210]. Sos (son of sevenless) is found to be a downstream signal transducer for sevenless but upstream of ras functioning as a guanine-nucleotide-exchanging factor [20, 212]. Studies on the vulval development of Caenorhabditis elegans also demonstrate that Ras (let-60) is required for EGFR (let-23) signal transduction [80]. Ras function is required for transmitting signals from NGF receptors and phorbol ester mitogens through Raf-1, mitogen-activated protein (MAP) kinase, and ribosomal $6 kinase (Rsk) (see below for a more detailed discussion). It is likely that Ras protein represents a converging point in the middle of the signal transduction pathways for RPTKs, nonreceptor PTKs, and probably phorbol-ester-activated PKC [ 134]. Downstream-Signaling Serine/Threonine Kinases Raf-1 is 74-kD protein serine/threonine kinase originally found as a retroviral oncoprotein [118, 183]. It becomes tyrosine-phosphorylated and physically associated with PDGFR upon its activation [155, 156]. Recent reports, however, indicate that Raf can be activated through the IR without accompanying tyrosine-phosphorylation [14, 108], suggesting that Raf-1 may not be a direct substrate of IR tyrosine kinase although it may be involved in the IR signal transduction pathway. The earliest evidence suggesting Raf-I as a downstream signal transducer for ras and src came from microinjection of anti-Ras antibodies [215]. Those neutralizing antibodies blocked the activity of Ras and tyrosine kinase signaling of v-Src and v-Fms but not v-Raf, implying that raflies downstream of ras, src and fms. Phosphorylation and kinase activity of pp74c-raf are increased in cells transformed by src-like oncogenes [I 55]. However, c-Raf lacks SH2 and SH3 domains, so its activation and phosphorylation by src-like PTKs may not take place by direct physical association. Antisense RNA for c-raf-1 and expression of kinase-defective raf-I inhibited serum-induced NIH 3T3 cell proliferation and blocked ras-induced cell transformation [ 107]. This study provided direct evidence that Raf-1 is a signal transducer downstream of Ras. Microinjection of dominant negative rafil RNA into Xenopus embryos blocked mesoderm induction by basic FGF (bFGF), suggesting that Raf-1 mediates bFGF receptor downstream signaling [ 127]. MAP kinases represent another family of serine/ threonine kinases involved in signal transduction by tyrosine kinases and PKC [226]. Though commonly referred to as MAP kinase, the enzyme is also known as extracellular-signal-regulated kinase (Erk) or mitosis-promoting kinase (MPK) [15]. There are several forms of MAP
kinases, p44 mapk (Erkl) and p42 mapk (Erk2) [19, 226]. Growth factors like insulin, EGF, NGF and phorbol esters activate MAP kinase by increasing its tyrosine- and threonine-phosphorylation. Activated MAP kinase then phosphorylates another serine/threonine kinase, Rsk [30, 67, 219]. A fraction of the activated MAP kinase and Rsk enters the nucleus [15, 30]. MAP kinase has been shown to phosphorylate c-Jun and activate its transactivating activity [ 181 ]. MEK1, also known as Erk kinase or MAP kinase kinase (MKK), is a protein tyrosine/threonine kinase which has long been suspected to phosphorylate MAP kinase, and has recently been purified and molecularly cloned [42, 43, 67]. MEK1 expressed in bacteria can phosphorylate Erk at tyrosine and threonine residues [43]. Purified MKK from PC 12 cells was activated by tyrosine/threonine phosphorylation after NGF stimulation [67]. MKK may be a substrate for Raf-1 kinase since it has been shown that Raf-1 can activate purified MKK in vitro. The MAP kinases (Erkl and Erk2) and MKK are constitutively activated in v-raf-transformed fibroblasts [81, 113]. Signaling Proteins with No Catalytic Domains Crk represents the prototype of a class of proteins which have only SH2 and/or SH3 sequences while lacking catalytic domains. In v-crk-transformed cells, tyrosinephosphorylation of a number of proteins is apparently elevated [140, 145]. The Crk oncoprotein may act as an adaptor to bridge a PTK with certain substrates, or it may prevent PTPase from dephosphorylating PTKs, locking them in the active state. The p85 subunit of PI3K contains SH2 and SH3 domains, while the catalytic activity of PI3K resides in p110 [78]. The p85 subunit serves as a regulator of PI3K. It has been documented that many activated RPTKs and src-like kinases associate with and activate the PI3K through binding to the SH2 domain of the p85 subunit [25, 97, 106, 126]. The p85 subunit appears to function as a 'docking' protein to affix the catalytic p110 of PI3K to tyrosine-phosphorylated RPTKs or to the SH2 domains of src-like PTKs. In addition to crk and the p85 subunit of PI3K, more and more SH2-and SH3-containing proteins have been identified recently. The human Nck cDNA codes for a cytoplasmic protein of 377 aa which contains one SH2 and three SH3 domains but has no catalytic sequences [115]. Overexpression of Nck caused transformation of 3Y1 rat fibroblasts and NIH 3T3 ceils [31, 119]. Nck is physically associated with EGFR, PDGFR, pp60 v-srcand cytoplasmic serine/threonine kinases [31, 119]. Phos-
73
phorylation of Nck on serine and tyrosine residues is increased in response to phorbol ester, cAMP, and a variety of receptors including EGFR, PDGFR, NGFR, T cell receptor, B cell receptor and Fc receptor [t 19, 148, 173]. However, total phosphotyrosine levels in the transformed 3Y1 fibroblasts were not elevated [31]. These studies suggest that Nck plays an important role in the control of cell growth. Another putative signaling protein, Shc, was isolated from a cDNA library of Burkitt lymphoma cells [178]. Similarly, Shc cDNA encodes an SH2-containing protein with no identifiable catalytic sequence. The Shc protein also contains an al-collagen-like domain. Shc is tyrosinephosphorylated by and associated with EGFR through its SH2 domain. Shc may also be a cellular substrate for v-src and v-fps [125]. Overexpression of Shc in NIH 3T3 cells resulted in their transformation, and the transformed cells can form tumors in nude mice. These data suggest that Shc may function in src, fps, EGFR and probably other RPTK-signaling pathways. It may play an important role in the mitogenic activities of those PTKs. Unlike v-Crk, Shc-transformed cells do not demonstrate a pronounced increase in tyrosine-phosphorylation of cellular proteins, even though Shc itself is heavily tyrosine-phosporylated by activated EGFR. This suggests that Shc might associate with some signaling proteins different from those complexed with the Crk protein. A new SH2/SH3-containing cDNA, Grb2/Ash was isolated recently which again has no catalytic sequences [ 123, 139]. Human Grb2 (growth-factor-binding protein 2) and rat Ash (abundant src homology) cDNAs encode a protein of about 25 kD with identical aa sequences. This 25-kD protein binds to activated EGFR, PDGFR, but not FGFR, through its SH2 domain. It appears to be a homolog of the sere-5 gene of the C. elegans, which is involved in the let-23 (EGFR-like) and let-60 (ras-like) signaling pathway crucial for the vulval development of C. elegans [33]. Indeed, Grb2/Ash protein seems to be involved in ras mitogenic signaling since coinjecting Grb2 and normal ras can induce DNA synthesis of quiescent REF-52 cells [123]. Consistent with this result, antisense Ash cDNA interferes with 3Y1 cell growth [ 139]. There have been recent reports that Grb2, Shc, Sos and p21 ras can form complexes [22, 50, 62, 117, 192, 193]. Formation of the complex was triggered by activation of tyrosine kinases like EGFR. The complex formation by Grb2, Shc, Sos and p21 ras in response to tyrosine kinase activation provides strong evidence for the link between RPTK and the ras signaling pathway. Genetic studies on Drosophila eye development also demonstrated that Drk
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(downstream-of-receptor kinases) protein, a Drosophila homolog of mammalian Grb2, functions downstream of Sevenless, a Ros-like RPTK [170, 211]. The SH3 domain of Drk was shown to bind to the proline-rich sequence in the tail of Sos, while the SH2 domain of Drk binds to a phosphotyrosine motif on the activated PTK receptor on the membrane [170, 213]. This interaction may help Sos gain access to the membrane-associated Ras and might also enhance the guanine-nucleotide-exchanging activity of Sos [170, 213]. The Vav proto-oncogene product (95 kD) perhaps represents a new class of signaling proteins that contain SH2 and SH3 domains. The ray oncogene was initially isolated from esophageal carcinoma genomic DNA fragments by gene transfer assay [38, 96]. Loss of the N-terminal sequence activates the oncogenicity of the vav protooncogene [95]. The ray proto-oncogene is exclusively expressed in hematopoietic cells. The Vav protein becomes rapidly tyrosine-phosphorylated when T or B cell antigen receptors are activated [23, 24, 130]. In addition, activation of EGFR or PDGFR leads to a marked increase in tyrosine phosphorylation of the p95 ray. Vav also directly associates with activated EGFR through its SH2 domain [130]. These studies suggest that Vav may serve as a messenger molecule for certain RPTKs in the hematopoietic cells. Interestingly, a group of transcription factors involved in interferon (IFN) signal transduction, ISGF-3a (pl 13, p91/84), were found to have SH2 and SH3 domains. These transcription factors have been shown to be tyrosine-phosphorylated in response to IFN-a stimulation [58, 59]. The tyrosine-phosphorylation is necessary for the formation of an active transcription complex. A cytoplasmic tyrosine kinase, tyk2, might be the putative enzyme that is involved in the IFN-a/[3 signaling pathway [233]. Another possible member of this family is HS1, a 75-kD protein strictly expressed in hematopoietic cells [102]. The cDNA product of HS 1 contains a helix-loop domain at its N-terminus and an SH3 domain at its C-terminus. It was recently demonstrated that the HS 1 protein was tyrosine-phosphorylated by and associated with a src-like PTK, Lyn, in activated B cells [257]. HSI may play an important role in signal transduction in hematopoietic cells. With the special structural features mentioned above, ISGF-3a and HS1 may represent a new class of signal transducers that transmit signals from the cell membrane to the nucleus. Even though the SH2-and SH3-containing proteins are favored for signal transduction and protein-protein interactions, a totally different signal transducer, IR substrate-
SignalTransductionby Protein Tyrosine Kinases
1 (IRS-1), may represent a prototype of yet another new family of signaling proteins. The IRS-1 cDNA was originally cloned from a rat liver cDNA library, and codes for a protein component of 185 kD that has been shown to be the major substrate for IR PTK [164, 222]. IRS-1 has neither SH2/SH3 nor catalytic domains. However, it contains over ten tyrosine phosphorylation sites, eight of which are YMXM or YXXM motifs [207, 222]. The tyrosine-phosporylated YXXM and YMXM motifs have been shown to mediate binding of SH2 domains of GAP and PI3K to activated tyrosine kinase receptors [54, 207]. IRS-1 binds to IR and to PI3K in response to insulin stimulation [158,207]. The IRS-1 binding site was mapped to the IR juxtamembrane region [5, 6]. Binding of IRS-1 to the SH2 domain of the PI3K subunit p85 can directly activate PI3K activity in vitro [158]. Thus, IRS-1 may serve as a multivalent bridging protein that connects signaling partners in a complex. It is conceivable that more IRS- l-like proteins will be identified in the near future.
sine-phosphorylation of proteins creates sites for SH2 binding and provides a mechanism for reversible regulation of signal transduction. Although cloning and characterization of the cellular proteins discussed above have provided a wealth of valuable information of PTK signal transduction, many questions remain unanswered. Given the fact that several PTKs (EGFR, PDGFR, pp60 src) can signal through the same downstream molecules (Grb2, Shc, Sos, Ras), how is the specificity of growth signal from each PTK receptor achieved? How does one cell regulate its response to different signals (metabolic versus mitogenic, differentiation versus proliferation)? What is the function of the products of PI3K? Activation of PTKs like EGFR and Src results in tyrosine-phosphorylation of many cellular proteins. What are the identities and functions of those proteins? Further studies on these SH2/SH3-containing proteins and IRSl-like proteins as well as those tyrosine-phosphorylated proteins with unassigned functions will certainly shed more light on the mechanisms for PTK signal transduction.
Concluding Remarks Genetic and biochemical studies of PTKs have allowed us to gradually construct a network of their signal transduction (fig. 1). Extracellular signals from growth factors, such as EGF, PDGF, IGF-1, insulin, CSF-1, HGF, NGF, MGF, and Neu differentiation factor, are first received by transmembrane PTK receptors. Activation of the receptor PTKs upon ligand binding results in autophosphorylation of the receptors themselves and tyrosine-phosphorylation of their cellular substrates. Several cellular targets, such as GAP, PLC-y, PI3K, IRS-1, Shc, Grb2, and Nck, have been found to function downstream of receptor PTKs. Genetic evidence from studies of C. elegans and Drosophila, in conjunction with biological and biochemical evidence from studies of EGFR and PDGFR strongly suggest that the SH2/SH3-containing 'adaptor' proteins, such as Grb2 and Shc, function downstream of receptor PTKs like EGFR, PDGFR, and Sevenless. A guanidine-nucleotide-exchange factor, Sos, residing in a signaling complex with Grb2, Shc, and p21 ras, provides a link between upstream PTKs and the downstream Ras protein. The serine/threonine kinase, Raf-1, may function further downstream and modulate the activity of Thr/Tyr kinases like MKK (MEK). Phosphorylation of MAP kinase (Erk) and Rsk leads to their activation and translocation into the cell nucleus, resulting in altered gene expression. The modular domains like SH2 and SH3 are implicated in mediating the protein-protein interaction. Tyro-
Acknowledgments This work has been supported by NIH grants CA29339 and CA55054and a grant from AaronDiamondFoundation.
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Signal Transduction by Protein Tyrosine Kinases
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