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Tyrosine kinase signalling in breast cancer: Tyrosine kinase-mediated signal transduction in transgenic mouse models of human breast cancer
Breast Cancer Researchvolume 2, Article number: 211 (2000)
The ability of growth factors and their cognate receptors to induce mammary epithelial proliferation and differentiation is dependent on their ability to activate a number of specific signal transduction pathways. Aberrant expression of specific receptor tyrosine kinases (RTKs) has been implicated in the genesis of a significant proportion of sporadic human breast cancers. Indeed, mammary epithelial expression of activated RTKs such as ErbB2/neu in transgenic mice has resulted in the efficient induction of metastatic mammary tumours. Although it is clear from these studies that activation these growth factor receptor signalling cascades are directly involved in mammary tumour progression, the precise interaction of each of these signalling pathways in mammary tumourigenesis and metastasis remains to be elucidated. The present review focuses on the role of several specific signalling pathways that have been implicated as important components in RTK-mediated signal transduction. In particular, it focuses on two well characterized transgenic breast cancer models that carry the polyomavirus middle T(PyV mT) and neu oncogenes.
The ability of mammary epithelial cells to respond to growth factor is dependent on specific growth factor receptors that are coupled to a number of intracellular signalling pathways. Of relevance to this is that the development, maturation and differentiation of the mammary epithelial cell are dependent on the interplay of hormones and growth factors. The development of the mammary gland is thought to involve a series of defined steps that consist of cell proliferation, differentiation and programmed cell death (apoptosis). After of the formation of the primary mammary tree from its embryonic rudiment, there is a rapid expansion of ductal outgrowth through the mammary fat pad, which is accompanied by the formation of mammary terminal end-buds. By 10 weeks of age the mammary epithelium has reached the end of the fat pad and ceases further ductal outgrowth.
After pregnancy, a further rapid expansion of the lobuloalveolar epithelium occurs, which leads to induction of terminal differentiation and lactation at birth. After the pups have been weaned from the lactating mother, the mammary epithelium undergoes a rapid involution through the induction of programmed cell death (apoptosis). The balance of soluble growth factors, hormones and cell substratum interactions controls the regulation of this cycle of proliferation, differentiation and apoptosis. Of particular relevance to these processes is the activity of the tyrosine kinase class of receptors that are thought play a key role in transducing these various extracellular signals. Elevated activity of certain tyrosine kinases can result in aberrant cell proliferation and ultimately cell transformation.
The present review examines the role of certain tyrosine kinases that have been implicated in mammary tumour progression.
Involvement of the Neu receptor tyrosine kinase in mammary tumourigenesis
The progression of the primary mammary epithelial cell to a malignant phenotype involves multiple genetic events, including the activation of dominant activating oncogenes and inactivation of specific tumour suppressor genes. Of relevance to the present review is the observation that the activation of certain RTKs is implicated in the genesis of human breast cancer. For example, amplification and over-expression of neu/erbB2 proto-oncogene is observed in 20-30% human breast cancer, and is inversely correlated with the survival of the patient [1,2**,3]. Although amplification and elevated expression of neu has been established as an important event in sporadic breast cancer, comparatively little is known concerning the molecular mechanism by which activation of neu influences mammary tumourigenesis and metastasis.
Direct evidence in support of a role for neu in mammary tumourigenesis is derived from observations made in transgenic mice that express oncogenic forms of the neu oncogene under the transcriptional control of mouse mammary tumour virus (MMTV) enhancer. Mammary epithelial specific expression of activated neu results in the rapid induction of metastatic multifocal mammary tumours [4,5,6**,7*]. Although mammary epithelial expression of the activated neu oncogene is tumourigenic, no comparable activating mutations have been detected in the transmembrane domain of human breast cancer that overexpresses ErbB2 . Thus, the primary mechanism by which ErbB2 induces mammary tumourigenesis in human breast cancer is through overexpression of the wild-type receptor.
The oncogenic potential of the wild-type neu proto-oncogene in the mammary epithelium was tested in transgenic mice through MMTV directed expression of the wild-type neu cDNA . These animals develop focal mammary tumours in 50% of female mice by age 205 days, with frequent metastases in the lung. Further genetic and biochemical analyses of these strains revealed that, in addition to elevated expression of tyrosine phosphorylated Neu, elevated levels of tyrosine phosphorylated ErbB3 were consistently observed [7*]. It is interesting to note that ErbB3 is the epidermal growth factor receptor family member that is primarily responsible for recruiting the phosphatidyl inositol-3 kinase (PI-3K) signalling molecule to Neu [10*,11*]. Given the importance of this signalling pathway in providing cell survival signals [12,13,14,15], it is conceivable that elevated expression of ErbB3 in these mammary tumours is required to provide the necessary antiapoptotic signals.
Another potent tyrosine kinase that is implicated in murine mammary tumourigenesis and metastasis is that associated with PyV mT antigen . Mammary epithelial expression of PyV mT results in the rapid induction of multifocal metastatic mammary tumours. Because these tumours occur early in mammary gland development and involve the entire mammary gland, expression of PyV mT is clearly sufficient for transformation of the primary mammary epithelium. The potent transforming activity of the PyV mT and neu oncogenes in the mammary epithelium of these transgenic strains is due to their capacity to associate with and activate a number of common signalling molecules. After activation of the associated tyrosine kinase activities of Neu and PyV mT, specific phosphotyrosine residues within these oncogenes provide specific binding sites for a variety of signalling molecules that harbour either SH2 or phosphotyrosine binding/interacting domains .
Activation of Src family kinases in mammary tumour progression
A class of signalling molecules that plays an important role in mammary tumourigenesis and metastasis is the Src family of tyrosine kinases. Both activated Neu and PyV mT form stable complexes with c-Src and c-Yes, resulting in an increase in the specific activity of these Src family kinases [17,18,19,20,21,22*,23,24,25,26,27*]. The importance of c-Src in PyV mT-mediated tumour progression has been demonstrated by crossing the MMTV/PyV mT strains to c-src-and c-yes-deficient mice [28**]. The results of that study demonstrated that c-Src was required for efficient mammary tumourigenesis and metastasis, whereas c-Yes function was dispensable for induction of mammary tumours. The difference in oncogenic potential between these crosses was not due to levels of tyrosine phosphorylated PyV mT, because the mammary tissue derived from each of the respective crosses had equal levels of tyrosine phosphorylated PyV mT. Although these observations argue that activation of c-Src function is a critical event in mammary tumour progression, mammary epithelial expression of an activated c-src oncogene in transgenic mice resulted in the induction of mammary epithelial hyperplasias rather than the multifocal mammary tumours observed in the PyV mT strains . Taken together, these observations argue that, although c-Src function is necessary for mammary tumour progression, its activation is not sufficient to induce the rapid tumour progression that is observed in the PyV mT transgenic strains.
Although it is clear that c-Src function is required for PyV mT-mediated tumourigenesis, its requirement for tumourigenesis in the Neu-induced model remains to be firmly established. Like PyV mT transformed tumour cells, however, c-Src derived from the Neu-induced mammary tumour cells is complexed with a 89-kDa phosphotyrosine protein that appears to be specific to the mammary epithelium . These observations suggest that activation of c-Src by either PyV mT or activated Neu may result in recruitment of similar sets of mammary specific substrates. Future crosses of the activated Neu strains with src-deficient strains should allow these issues to be addressed.
Activation of the phosphatidyl inositol-3 kinase in mammary tumour progression
Another class of SH2 signalling molecules that are known to be associated and activated by both PyV mT and activated Neu oncogenes is PI-3K. Association of PI-3K with PyV mT occurs through its binding to phosphotyrosine residues (Tyr 315/322) within the PyV mT coding sequences . In contrast, recruitment of the PI-3K by Neu occurs through the recruitment to ErbB3 [10*,11*]. Activation of PI-3K and consequent production of phosphoinotide-3 lipids stimulates a number of plekstrin homology-containing serine kinases, including PDK1 and integrin-linked kinase [31,32,33]. These activated serine kinases in turn activate the Akt/PKB class of serine kinases, which can stimulate a number of antiapoptotic signalling molecules such as nuclear factor-κB [34,35,36]. In addition, activation of Akt can inhibit proapoptotic proteins such as Bad, Forkhead transcription factors and caspase 9 [12,37,38].
The importance of the PI-3K signalling pathway has been highlighted by several recent studies. Mammary epithelial expression of mutant PyV mT decoupled from the PI-3K pathway results in the induction of extensive mammary epithelial hyperplasias . Consistent with the importance of the PI-3K signalling pathway in promoting cell survival, these mammary epithelial hyperplasias were highly apoptotic. Conversely, inducible expression of a dominant-negative inhibitor of PI-3K in mammary tumour cells expressing wild-type PyV mT was capable of efficiently inducing apoptotic cell death. Despite the initial induction of global mammary epithelial hyperplasias, focal mammary tumours eventually developed in these mammary strains. Mammary tumour progression in these mutant PyV mT strains was further correlated with a dramatic upregulation of the ErbB2 and ErbB3 RTKs. It is conceivable that elevated levels of ErbB2/ErbB3 can indirectly recruit the PI-3K, and thus compensate for the inability of the mutant PyV mT to associate and activate the PI-3K.
Another interesting phenotype of tumours that are induced by this mutant PyV mT is that they are poorly metastatic by comparison with tumours that express the wild-type PyV mT oncogene . The observed defect in the metastatic potential of mammary tumours induced by this mutant form of PyV mT was further correlated with a defect in neovascularization . Taken together, these observations argue that activation of the PI-3K PyV mT may play a critical role in promoting metastatic invasion.
Although activation of Neu is not directly associated with activation of the PI-3K signalling pathway, it can heterodimerize with ErbB3, which possesses six PI-3K binding sites. Indeed, it is thought that recruitment of the PI-3K signalling pathway by members of the epidermal growth factor receptor family is through heterodimerization with the ErbB3 RTK [10,11]. Given the importance of ErbB3 in recruiting the PI-3K signalling molecule, elevated expression of ErbB3 may be an important step in Neu-induced mammary tumourigenesis. Consistent with this view, elevated expression of ErbB3 is observed during mammary tumour progression in transgenic mice that express Neu in the mammary epithelium [7*]. Interestingly, the observed upregulation of ErbB3 protein in the Neu-induced mammary tumours does not occur at the level of erbB3 transcript, because both tumour and adjacent normal mammary tissue express comparable levels of erbB3 transcript [7*]. The precise molecular mechanism by which elevated levels of ErbB3 protein is achieved during mammary tumour progression remains to be elucidated, however. Consistent with these transgenic mouse studies, a large proportion of ErbB2-expressing human breast cancers exhibit elevated levels of erbB3 transcripts [7*]. Thus, coexpression of ErbB2 and ErbB3 RTKs appears to be common event in tumour progression in both humans and these transgenic mouse models.
Activation of the Ras signalling pathway in mammary tumour progression
Other cytoplasmic proteins such as Shc and Grb2 have been demonstrated to form specific complexes with both activated forms of Neu and PyV mT [40,41,42,43*,44,45,46,47,48*,49,50]. The association of Grb2 and Shc with either of these activated oncoproteins is known to play a central role in stimulation of Ras signalling. For example, tyrosine phosphorylation of Shc either by the PyV mT complex or by Neu results in an association with Grb2. In turn, Grb2 stimulates a guanine nucleotide exchange protein, SOS, to convert Ras from the inactive GDP-bound state to the active GTP-bound form [45,51,52,53,54,55,56]. In contrast to PyV mT, which signals to Ras through its association with Shc, Neu can activate Ras through Grb2, Shc and several other unidentified adapter proteins [46,57]. Upon Ras activation, it can associate with a number of downstream effector molecules including PI-3K, Raf serine kinase, GAP and Ral [58,59,60,61,62,63,64,65].
Direct evidence in support of a role for Ras in mammary tumour progression stems from observations made with transgenic mice that express an oncogenic version of Ras under transcriptional control of the MMTV promoter. Mammary epithelial-specific expression of v-Ha-ras resulted in the induction of focal mammary tumours in female transgene carriers [66**]. Because these tumours were focal in origin and arose after a long latency period, expression of activated ras is not sufficient to induce mammary tumours, but rather requires additional genetic events. Although insufficient for tumour induction alone, a growing body of evidence suggests that activation of the Ras signalling pathway is critical for the progression to the tumourigenic phenotype. For example, mammary-specific expression of a mutant PyV mT oncogene decoupled from the Shc/Grb2 signalling molecules results in the induction of widespread mammary epithelial hyperplasias . In contrast to the rapid tumour progression observed in the wild-type PyV mT transgenic mice, focal mammary tumours arise in the mutant PyV mT strains after a long latency period. Interestingly, a certain proportion of tumours that arise in these mutant PyV mT strains exhibit reversion of Shc-binding site mutation . The strong biological selection for retention of Shc-binding site suggests that retention of this signalling pathway is critical for tumour progression.
Further evidence in support of the importance of the Shc-Grb2-Ras signalling axis in mammary tumour progression stems from observations made by interbreeding the PyV mT transgenic strains with the Grb2 knockout mice. Because homozygous deletion of Grb2 is not compatible with embryonic viability [67*], it was not feasible to ascertain whether Grb2 function was absolutely required for PyV mT tumour progression. The results of those experiments, however, revealed that a reduction to one copy of Grb2 was sufficient to interfere with tumour progression [67*]. Conversely, ectopic expression of Grb2 or Shc in the mammary epithelium of transgenic mice cooperates with mutant PyV mT decoupled from the Shc adapter protein to accelerate mammary tumour progression . Taken together, these observations argue that dosage of these key adapter proteins that couple to Ras can have profound effects on mammary tumour progression.
Although studies with PyV mT transgenic mice have clearly demonstrated the importance of PI-3K, c-Src and Shc/Grb2/Ras signalling pathways in mammary tumourigenesis and metastasis [15,28**], the role of these various signalling molecules in Neu-induced tumourigenesis is less well understood. In contrast to the well-defined signalling molecules emanating from the PyV mT oncogene, the binding sites for only a subset of signalling molecules that couple to Neu have been identified. These include Grb2 and Shc molecules, which bind tyrosine residues 1144 and 1227 in Neu [43*]. In addition to these signalling molecules that positively activate the Ras signalling pathway, an autophosphorylation site that negatively regulates Neu-mediated signal transduction has also been described [43*]. The identity of this signalling molecule remains to be elucidated, however. Thus, unlike PyV mT, the signalling molecules that modulate the Ras signalling pathway are probably more complex in Neu-mediated tumourigenesis. Future studies to investigate the role of Neu-coupled signalling molecules in mammary tumour progression should provide important insight into the molecular basis of breast cancer.
The studies outlined above strongly support the notion that tyrosine kinase-mediated signalling in the mammary epithelium involves the concerted activation of a number of signalling pathways that can cooperate to lead to malignant transformation of the mammary epithelial cell. Future strategies to interfere with the ability of tyrosine kinases to transform cells will independently target these coupled signalling pathways. The development of novel inhibitors of these signalling molecules will hopefully provide effective treatment for this prevalent, but poorly understood disease.
Andrulis IL, Bull SB, Blackstein ME, et al: neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. Toronto Breast Cancer Study Group. J Clin Oncol. 1998, 16: 1340-1349.
Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: correlation of relapse and survival with the amplification of the HER2/neu oncogene. Science. 1987, 235: 177-182. This paper implicated amplification status of ErbB2 as an important prognostic marker in human breast cancer
Slamon DJ, Godolphin W, Jones LA, et al: Studies of the HER-2/neu proto-oncogene in human breast and ovaian cancer. Science. 1989, 244: 707-712.
Guy CT, Cardiff RD, Muller WJ: Activated neu induces rapid tumor progression. J Biol Chem. 1996, 271: 7673-7678. 10.1074/jbc.271.16.9567.
Lucchini F, Sacco MG, Hu N, et al: Early and multifocal tumors in breast, salivary, harderian and epididymal tissues developed in MMTY-Neu transgenic mice. Cancer Lett. 1992, 64: 203-209. 10.1016/0304-3835(92)90044-V.
Muller WJ, Sinn E, Pattengale PK, Wallace R, Leder P: Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell. 1988, 54: 105-115. This paper provided the first direct evidence that ErbB2 is causally involved in mammary tumour progression.
Siegel PM, Ryan ED, Cardiff RD, Muller WJ: Elevated expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer. EMBO J. 1999, 18: 2149-2164. 10.1093/emboj/18.8.2149. This paper implicated coexpression of ErbB2 and ErbB3 as a prevalent event in mammary tumour progression.
Lemoine NR, Staddon S, Dickson C, Barnes DM, Gullick WJ: Absence of activating transmembrane mutations in the c-erbB-2 proto-oncogene in human breast cancer. Oncogene. 1990, 5: 237-239.
Guy CT, Webster MA, Schaller M, et al: Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA. 1992, 89: 10578-10582.
Prigent SA, Gullick WJ: Identification of c-erbB-3 binding sites for phosphatidylinositol 3'-kinase and SHC using an EGF receptor/c-erbB-3 chimera. EMBO J. 1994, 13: 2831-2841. This paper provided evidence that erbB-3 is primarily involved in recruitment of the PI-3K signalling molecule.
Soltoff SP, Carraway KL, Prigent SA, Gullick WG, Cantley LC: ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor. Mol Cell Biol. 1994, 14: 3550-3558. Evidence is provided that the primary role of ErbB-3 is to recruit the PI-3K pathway to other EGF receptor family members.
Brunet A, Bonni A, Zigmond MJ, et al: Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999, 96: 857-868.
Dahl J, Jurczak A, Cheng LA, Baker DC, Benjamin TL: Evidence of a role for phosphatidylinositol 3-kinase activation in the blocking of apoptosis by polyomavirus middle T antigen. J Virol. 1998, 72: 3221-3226.
Franke TF, Kaplan DR, Cantley LC: PI3K: downstream AKTion blocks apoptosis. Cell. 1997, 88: 435-437. 10.1016/S0092-8674(00)81883-8.
Webster MA, Hutchinson JN, Rauh MJ, et al: Requirement for both Shc and phosphatidylinositol 3' kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis. Mol Cell Biol. 1998, 18: 2344-2359.
Guy CT, Cardiff RD, Muller WJ: Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol. 1992, 12: 954-961.
Pawson T: Protein modules and signalling networks. Nature. 1995, 373: 573-580. 10.1038/373573a0.
Cheng SH, Harvey R, Espino PC, et al: Peptide antibodies to the human c-fyn gene product demonstrate pp59c-fyn is capable of complex formation with the middle-T antigen of polyomavirus. EMBO J. 1988, 7: 3845-3855.
Courtneidge SA, Smith AE: The complex of polyoma virus middle-T antigen and pp60c-src. EMBO J. 1984, 3: 585-591.
Kornbluth S, Sudol M, Hanafusa H: Association of the polyomavirus middle-T antigen with c-yes protein. Nature. 1987, 325: 171-173. 10.1038/325171a0.
Kypta RM, Hemming A, Courtneidge SA: Identification and characterization of p59fyn (a src-like protein tyrosine kinase) in normal and polyoma virus transformed cells. EMBO J. 1988, 7: 3837-3844.
Luttrell DK, Lee A, Lansing TJ, et al: Involvement of pp60c-src with two major signaling pathways in human breast cancer. Proc Natl Acad Sci USA. 1994, 91: 83-87. Evidence is provided that links activation of the c-Src signalling molecule with human breast cancer cells that express elevated levels of epidermal growth factor receptor and ErbB2.
Luttrell LM, Hawes BE, van Biesen T, et al: Role of c-Src tyrosine kinase in G protein-coupled receptor- and Gbetagamma subunit-mediated activation of mitogen-activated protein kinases. J Biol Chem. 1996, 271: 19443-19450. 10.1074/jbc.271.21.12133.
Muthuswamy SK, Muller WJ: Activation of Src family kinases in Neu-induced mammary tumors correlates with their association with distinct sets of tyrosine phosphorylated proteins in vivo. Oncogene. 1995, 11: 1801-1810.
Muthuswamy SK, Muller WJ: Activation of the Src family of tyrosine kinases in mammary tumorigenesis. Adv Cancer Res. 1994, 64: 111-123.
Muthuswamy SK, Muller WJ: Direct and specific interaction of c-Src with Neu is involved in signaling by the epidermal growth factor receptor. Oncogene. 1995, 11: 271-279.
Muthuswamy SK, Siegel PM, Dankort DL, Webster MA, Muller WJ: Mammary tumors expressing the neu proto-oncogene possess elevated c-Src tyrosine kinase activity. Mol Cell Biol. 1994, 14: 735-743. This paper suggested that the src tyrosine kinase is involved in ErbB2-mediated tumour progreession.
Guy CT, Muthuswamy SK, Cardiff RD, Soriano P, Muller WJ: Activation of the c-Src tyrosine kinase is required for the induction of mammary tumors in transgenic mice. Genes Dev. 1994, 8: 23-32. This paper provided direct genetic evidence that c-Src is a critical signalling pathway in mammary tumour progression
Webster MK, Donoghue DJ: Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia. EMBO J. 1996, 15: 520-527.
Courtneidge SA, Heber A: An 81 kd protein complexed with middle T antigen and pp60c-src: a possible phosphatidylinositol kinase. Cell. 1987, 50: 1031-1037.
Alessi DR, Deak M, Casamayor A, et al: 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Curr Biol. 1997, 7: 776-789. 10.1016/S0960-9822(06)00336-8.
Bellacosa A, Chan TO, Ahmed NN, et al: Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene. 1998, 17: 313-325. 10.1038/sj.onc.1201947.
Delcommenne M, Tan C, Gray V, et al: Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci USA. 1998, 95: 11211-11216. 10.1073/pnas.95.19.11211.
Eskew JD, Vanacore RM, Sung L, Morales PJ, Smith A: Cellular protection mechanisms against extracellular heme. heme- hemo-pexin, but not free heme, activates the N-terminal c-jun kinase. J Biol Chem. 1999, 274: 638-648. 10.1074/jbc.274.2.638.
Kane LP, Shapiro VS, Stokoe D, Weiss A: Induction of NF-kappaB by the Akt/PKB kinase. Curr Biol. 1999, 9: 601-604. 10.1016/S0960-9822(99)80265-6.
Sizemore N, Leung S, Stark GR: Activation of phosphatidylinositol 3-kinase in response to interleukin- 1 leads to phosphorylation and activation of the NF-kappaB p65/RelA subunit. Mol Cell Biol. 1999, 19: 4798-4805.
Cardone MH, Roy N, Stennicke HR, et al: Regulation of cell death protease caspase-9 by phosphorylation. Science. 1998, 282: 1318-1321. 10.1126/science.282.5392.1318.
Datta SR, Dudek H, Tao X, et al: Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997, 91: 231-241. 10.1016/S0092-8674(00)80405-5.
Cheung A, Young L, Chen P, et al: Microcirculation and metastasis in a new mouse mammary tumor model system. Int J Oncol. 1997, 11: 235-241.
Ben-Levy R, Paterson HF, Marshall CJ, Yarden Y: A single autophosphorylation site confers oncogenicity to the Neu/ErbB-2 receptor and enables coupling to the MAP kinase pathway. EMBO J. 1994, 13: 3302-3311.
Blaikie PA, Fournier E, Dilworth SM, et al: The role of the Shc phosphotyrosine interaction/phosphotyrosine binding domain and tyrosine phosphorylation sites in polyoma middle T antigen-mediated cell transformation. J Biol Chem. 1997, 272: 20671-20677. 10.1074/jbc.272.33.20671.
Campbell KS, Ogris E, Burke B, et al: Polyoma middle tumorantigen interacts with SHC protein via the NPTY (Asn-Pro-Thr-Tyr) motif in middle tumor antigen. Proc Natl Acad Sci USA. 1994, 91: 6344-6348.
Dankort DL, Wang Z, Blackmore V, Moran MF, Muller WJ: Distinct tyrosine autophosphorylation sites negatively and positively modulate neu-mediated transformation. Mol Cell Biol. 1997, 17: 5410-5425. This paper provided evidence of multiple functional redundant signalling pathways from the ErbB2 RTK.
Dilworth SM, Brewster CE, Jones MD, et al: Transformation by polyoma virus middle T-antigen involves the binding and tyrosine phosphorylation of Shc. Nature. 1994, 367: 87-90. 10.1038/367087a0.
Gale NW, Kaplan S, Lowenstein EJ, Schlessinger J, Bar-Sagi D: Grb2 mediates the EGF-dependent activation of guanine nucleotide exchange on Ras. Nature. 1993, 363: 88-92. 10.1038/363088a0.
Janes PW, Daly RJ, deFazio A, Sutherland RL: Activation of the Ras signalling pathway in human breast cancer cells overexpressing erbB-2. Oncogene. 1994, 9: 3601-3608.
Janes PW, Lackmann M, Church WB, et al: Structural determinants of the interaction between the erbB2 receptor and the Src homology 2 domain of Grb7. J Biol Chem. 1997, 272: 8490-8497. 10.1074/jbc.272.13.8490.
Niemann C, Brinkmann V, Spitzer E, et al: Reconstitution of mammary gland development in vitro: requirement of c-met and c-erbB2 signaling for branching and alveolar morphogenesis. J Cell Biol. 1998, 143: 533-545. 10.1083/jcb.143.2.533. This paper provided evidence that normal mammary gland morphogenesis is dependent on integration of both Met- and ErbB2-coupled signals.
Pelicci G, Lanfrancone L, Grignani F, et al: A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell. 1992, 70: 93-104.
Ricci A, Lanfrancone L, Chiari R, et al: Analysis of protein-protein interactions involved in the activation of the Shc/Grb-2 pathway by the ErbB-2 kinase. Oncogene. 1995, 11: 1519-1529.
Chardin P, Camonis JH, Gale NW, et al: Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science. 1993, 260: 1338-1343.
Egan SE, Giddings BW, Brooks MW, et al: Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature. 1993, 363: 45-51. 10.1038/363045a0.
Li N, Batzer A, Daly R, et al: Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature. 1993, 363: 85-88. 10.1038/363085a0.
Lowenstein EJ, Daly RJ, Batzer AG, et al: The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell. 1992, 70: 431-42.
Rozakis-Adcock M, Fernley R, Wade J, Pawson T, Bowtell D: The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSos1. Nature. 1993, 363: 83-85. 10.1038/363083a0.
Rozakis-Adcock M, McGlade J, Mbamalu G, et al: Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases. Nature. 1992, 360: 689-692. 10.1038/360689a0.
Xie Y, Pendergast AM, Hung MC: Dominant-negative mutants of Grb2 induced reversal of the transformed phenotypes caused by the point mutation-activated rat HER-2/Neu. J Biol Chem. 1995, 270: 30717-30724. 10.1074/jbc.270.30.18123.
Hallberg B, Rayter SI, Downward J: Interaction of Ras and Raf in intact mammalian cells upon extracellular stimulation. J Biol Chem. 1994, 269: 3913-3916.
Kikuchi A, Demo SD, Ye ZH, Chen YW, Williams LT: ralGDS family members interact with the effector loop of ras p21. Mol Cell Biol. 1994, 14: 7483-7491.
Marshall CJ: Ras effectors. Curr Opin Cell Biol. 1996, 8: 197-204. 10.1016/S0955-0674(96)80066-4.
McCormick F, Martin GA, Clark R, Bollag G, Polakis P: Regulation of ras p21 by GTPase activating proteins. Cold Spring Harb Symp Quant Biol. 1991, 56: 237-241.
Rodriguez-Viciana P, Marte BM, Warne PH, Downward J: Phosphatidylinositol 3' kinase: one of the effectors of Ras. Phil Trans R Soc Lond B Biol Sci. 1996, 351: 225-231; discussion 231-232.
Troppmair J, Bruder JT, Munoz H, et al: Mitogen-activated protein kinase/extracellular signal-regulated protein kinase activation by oncogenes, serum, and 12-O-tetradecanoylphorbol-13- acetate requires Raf and is necessary for transformation. J Biol Chem. 1994, 269: 7030-7035.
Warne PH, Viciana PR, Downward J: Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature. 1993, 364: 352-355. 10.1038/364352a0.
Zheng Y, Bagrodia S, Cerione RA: Activation of phosphoinositide 3-kinase activity by Cdc42Hs binding to p85. J Biol Chem. 1994, 269: 18727-18730.
Sinn E, Muller W, Pattengale P, Tepler I, Wallace R, Leder P: Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo. Cell. 1987, 49: 465-475. This paper was one of the first to document cooperation of two independent oncogene-coupled signalling pathways in mammary tumour progression.
Cheng AM, Saxton TM, Sakai R, et al: Mammalian Grb2 regulates multiple steps in embryonic development and malignant transformation. Cell. 1998, 95: 793-803. This report provided evidence suggesting that the levels of Grb2/Ras pathway was critical in mammary tumour progression.
Rauh MJ, Blackmore V, Andrechek ER, et al: Accelerated mammary tumor development in mutant polyomavirus middle T transgenic mice expressing elevated levels of either the Shc or Grb2 adapter protein. Mol Cell Biol. 1999, 19: 8169-8179.
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