Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Communication
  • Published:

The ShcA SH2 domain engages a 14-3-3/PI3′K signaling complex and promotes breast cancer cell survival

Oncogene volume 31, pages 5038–5044 (2012)Cite this article

Subjects

Abstract

The ShcA adapter protein transmits activating signals downstream of receptor and cytoplasmic tyrosine kinases through the establishment of phosphotyrosine-dependent complexes. In this regard, ShcA possesses both a phosphotyrosine-binding domain (PTB) and Src homology 2 domain (SH2), which bind phosphotyrosine residues in a sequence-specific manner. Although the majority of receptor tyrosine kinases expressed in breast cancer cells bind the PTB domain, very little is known regarding the biological importance of SH2-driven ShcA signaling during mammary tumorigenesis. To address this, we employed transgenic mice expressing a mutant ShcA allele harboring a non-functional SH2 domain (ShcR397K) under the transcriptional control of the endogenous ShcA promoter. Using transplantation approaches, we demonstrate that SH2-dependent ShcA signaling within the mammary epithelial compartment is essential for breast tumor outgrowth, survival and the development of lung metastases. We further show that the ShcA SH2 domain activates the AKT pathway, potentially through a novel SH2-mediated complex between ShcA, 14-3-3ζ and the p85 regulatory subunit of phosphatidylinositol 3 (PI3′) kinase. This study is the first to demonstrate that the SH2 domain of ShcA is critical for tumor survival during mammary tumorigenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Frackelton Jr AR, Lu L, Davol PA, Bagdasaryan R, Hafer LJ, Sgroi DC . p66 Shc and tyrosine-phosphorylated Shc in primary breast tumors identify patients likely to relapse despite tamoxifen therapy. Breast Cancer Res 2006; 8: R73.

    Article  Google Scholar 

  2. Davol PA, Bagdasaryan R, Elfenbein GJ, Maizel AL, Frackelton Jr AR . Shc proteins are strong, independent prognostic markers for both node-negative and node-positive primary breast cancer. Cancer Res 2003; 63: 6772–6783.

    CAS  PubMed  Google Scholar 

  3. Ursini-Siegel J, Cory S, Zuo D, Hardy WR, Rexhepaj E, Lam S et al. Receptor tyrosine kinase signaling favors a protumorigenic state in breast cancer cells by inhibiting the adaptive immune response. Cancer Res 2010; 70: 7776–7787.

    Article  CAS  Google Scholar 

  4. Ursini-Siegel J, Hardy WR, Zuo D, Lam SH, Sanguin-Gendreau V, Cardiff RD et al. ShcA signalling is essential for tumour progression in mouse models of human breast cancer. EMBO J 2008; 27: 910–920.

    Article  CAS  Google Scholar 

  5. Alimandi M, Romano A, Curia MC, Muraro R, Fedi P, Aaronson SA et al. Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas. Oncogene 1995; 10: 1813–1821.

    CAS  PubMed  Google Scholar 

  6. Batzer AG, Blaikie P, Nelson K, Schlessinger J, Margolis B . The phosphotyrosine interaction domain of Shc binds an LXNPXY motif on the epidermal growth factor receptor. Mol Cell Biol 1995; 15: 4403–4409.

    Article  CAS  Google Scholar 

  7. 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.

    Article  CAS  Google Scholar 

  8. Gillgrass A, Cardiff RD, Sharan N, Kannan S, Muller WJ . Epidermal growth factor receptor-dependent activation of Gab1 is involved in ErbB-2-mediated mammary tumor progression. Oncogene 2003; 22: 9151–9155.

    Article  CAS  Google Scholar 

  9. Ishiguro Y, Iwashita T, Murakami H, Asai N, Iida K, Goto H et al. The role of amino acids surrounding tyrosine 1062 in ret in specific binding of the shc phosphotyrosine-binding domain. Endocrinology 1999; 140: 3992–3998.

    Article  CAS  Google Scholar 

  10. Jones RA, Campbell CI, Wood GA, Petrik JJ, Moorehead RA . Reversibility and recurrence of IGF-IR-induced mammary tumors. Oncogene 2009; 28: 2152–2162.

    Article  CAS  Google Scholar 

  11. 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.

    Article  CAS  Google Scholar 

  12. Vijapurkar U, Cheng K, Koland JG . Mutation of a Shc binding site tyrosine residue in ErbB3/HER3 blocks heregulin-dependent activation of mitogen-activated protein kinase. J Biol Chem 1998; 273: 20996–21002.

    Article  CAS  Google Scholar 

  13. Zhang Z, Kumar R, Santen RJ, Song RX . The role of adapter protein Shc in estrogen non-genomic action. Steroids 2004; 69: 523–529.

    Article  CAS  Google Scholar 

  14. 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.

    Article  CAS  Google Scholar 

  15. Lin EY, Jones JG, Li P, Zhu L, Whitney KD, Muller WJ et al. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol 2003; 163: 2113–2126.

    Article  Google Scholar 

  16. Webster MA, Hutchinson JN, Rauh MJ, Muthuswamy SK, Anton M, Tortorice CG 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.

    Article  CAS  Google Scholar 

  17. Rauh MJ, Blackmore V, Andrechek ER, Tortorice CG, Daly R, Lai VK 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.

    Article  CAS  Google Scholar 

  18. Hardy WR, Li L, Wang Z, Sedy J, Fawcett J, Frank E et al. Combinatorial ShcA docking interactions support diversity in tissue morphogenesis. Science 2007; 317: 251–256.

    Article  CAS  Google Scholar 

  19. Barry EF, Felquer FA, Powell JA, Biggs L, Stomski FC, Urbani A et al. 14-3-3:Shc scaffolds integrate phosphoserine and phosphotyrosine signaling to regulate phosphatidylinositol 3-kinase activation and cell survival. J Biol Chem 2009; 284: 12080–12090.

    Article  CAS  Google Scholar 

  20. Rozakis-Adcock M, McGlade J, Mbamalu G, Pelicci G, Daly R, Li W 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.

    Article  CAS  Google Scholar 

  21. van der Geer P, Wiley S, Gish GD, Pawson T . The Shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (Y239/240) that mediate protein-protein interactions. Curr Biol 1996; 6: 1435–1444.

    Article  CAS  Google Scholar 

  22. Ling C, Zuo D, Xue B, Muthuswamy S, Muller WJ . A novel role for 14-3-3sigma in regulating epithelial cell polarity. Genes Dev 2010; 24: 947–956.

    Article  CAS  Google Scholar 

  23. Orlando FA, Brown KD . Unraveling breast cancer heterogeneity through transcriptomic and epigenomic analysis. Ann Surg Oncol 2009; 16: 2270–2279.

    Article  Google Scholar 

  24. Su CH, Zhao R, Zhang F, Qu C, Chen B, Feng YH et al. 14-3-3sigma exerts tumor-suppressor activity mediated by regulation of COP1 stability. Cancer Res 2011; 71: 884–894.

    Article  CAS  Google Scholar 

  25. Hodgson JG, Malek T, Bornstein S, Hariono S, Ginzinger DG, Muller WJ et al. Copy number aberrations in mouse breast tumors reveal loci and genes important in tumorigenic receptor tyrosine kinase signaling. Cancer Res 2005; 65: 9695–9704.

    Article  CAS  Google Scholar 

  26. Neal CL, Xu J, Li P, Mori S, Yang J, Neal NN et al. Overexpression of 14-3-3zeta in cancer cells activates PI3K via binding the p85 regulatory subunit. Oncogene 2011.

  27. Gotoh N, Tojo A, Shibuya M . A novel pathway from phosphorylation of tyrosine residues 239/240 of Shc, contributing to suppress apoptosis by IL-3. EMBO J 1996; 15: 6197–6204.

    Article  CAS  Google Scholar 

  28. Patrussi L, Savino MT, Pellegrini M, Paccani SR, Migliaccio E, Plyte S et al. Cooperation and selectivity of the two Grb2 binding sites of p52Shc in T-cell antigen receptor signaling to Ras family GTPases and Myc-dependent survival. Oncogene 2005; 24: 2218–2228.

    Article  CAS  Google Scholar 

  29. Gu H, Maeda H, Moon JJ, Lord JD, Yoakim M, Nelson BH et al. New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathway. Mol Cell Biol 2000; 20: 7109–7120.

    Article  CAS  Google Scholar 

  30. Bone H, Welham MJ . Shc associates with the IL-3 receptor beta subunit, SHIP and Gab2 following IL-3 stimulation. Contribution of Shc PTB and SH2 domains. Cell Signal 2000; 12: 183–194.

    Article  CAS  Google Scholar 

  31. Campbell KS, Ogris E, Burke B, Su W, Auger KR, Druker BJ et al. Polyoma middle tumor antigen 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.

    Article  CAS  Google Scholar 

  32. Cook RS, Garrett JT, Sanchez V, Stanford JC, Young C, Chakrabarty A et al. ErbB3 ablation impairs PI3K/Akt-dependent mammary tumorigenesis. Cancer Res 2011; 71: 3941–3951.

    Article  CAS  Google Scholar 

  33. Morrison DK . The 14-3-3 proteins: integrators of diverse signaling cues that impact cell fate and cancer development. Trends Cell Biol 2009; 19: 16–23.

    Article  CAS  Google Scholar 

  34. Backer JM, Myers Jr MG, Shoelson SE, Chin DJ, Sun XJ, Miralpeix M et al. Phosphatidylinositol 3′-kinase is activated by association with IRS-1 during insulin stimulation. EMBO J 1992; 11: 3469–3479.

    Article  CAS  Google Scholar 

  35. Zhou MM, Harlan JE, Wade WS, Crosby S, Ravichandran KS, Burakoff SJ et al. Binding affinities of tyrosine-phosphorylated peptides to the COOH-terminal SH2 and NH2-terminal phosphotyrosine binding domains of Shc. J Biol Chem 1995; 270: 31119–31123.

    Article  CAS  Google Scholar 

  36. Telles E, Hosing AS, Kundu ST, Venkatraman P, Dalal SN . A novel pocket in 14-3-3epsilon is required to mediate specific complex formation with cdc25C and to inhibit cell cycle progression upon activation of checkpoint pathways. Exp Cell Res 2009; 315: 1448–1457.

    Article  CAS  Google Scholar 

  37. Wang B, Liu K, Lin FT, Lin WC . A role for 14-3-3 tau in E2F1 stabilization and DNA damage-induced apoptosis. J Biol Chem 2004; 279: 54140–54152.

    Article  CAS  Google Scholar 

  38. Komiya Y, Kurabe N, Katagiri K, Ogawa M, Sugiyama A, Kawasaki Y et al. A novel binding factor of 14-3-3beta functions as a transcriptional repressor and promotes anchorage-independent growth, tumorigenicity, and metastasis. J Biol Chem 2008; 283: 18753–18764.

    Article  CAS  Google Scholar 

  39. Lu J, Guo H, Treekitkarnmongkol W, Li P, Zhang J, Shi B et al. 14-3-3zeta Cooperates with ErbB2 to promote ductal carcinoma in situ progression to invasive breast cancer by inducing epithelial-mesenchymal transition. Cancer Cell 2009; 16: 195–207.

    Article  CAS  Google Scholar 

  40. Neal CL, Yao J, Yang W, Zhou X, Nguyen NT, Lu J et al. 14-3-3zeta overexpression defines high risk for breast cancer recurrence and promotes cancer cell survival. Cancer Res 2009; 69: 3425–3432.

    Article  CAS  Google Scholar 

  41. George R, Schuller AC, Harris R, Ladbury JE . A phosphorylation-dependent gating mechanism controls the SH2 domain interactions of the Shc adaptor protein. J Mol Biol 2008; 377: 740–747.

    Article  CAS  Google Scholar 

  42. Dankort D, Maslikowski B, Warner N, Kanno N, Kim H, Wang Z et al. Grb2 and Shc adapter proteins play distinct roles in Neu (ErbB-2)-induced mammary tumorigenesis: implications for human breast cancer. Mol Cell Biol 2001; 21: 1540–1551.

    Article  CAS  Google Scholar 

  43. Dilworth SM, Griffin BE . Monoclonal antibodies against polyoma virus tumor antigens. Proc Natl Acad Sci USA 1982; 79: 1059–1063.

    Article  CAS  Google Scholar 

  44. Ranger JJ, Levy DE, Shahalizadeh S, Hallett M, Muller WJ . Identification of a Stat3-dependent transcription regulatory network involved in metastatic progression. Cancer Res 2009; 69: 6823–6830.

    Article  CAS  Google Scholar 

  45. Ursini-Siegel J, Rajput AB, Lu H, Sanguin-Gendreau V, Zuo D, Papavasiliou V et al. Elevated expression of DecR1 impairs ErbB2/Neu-induced mammary tumor development. Mol Cell Biol 2007; 27: 6361–6371.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr Peter Siegel for critical reading of this manuscript and Vasilios Papavasiliou for assisting with the injection studies. This work was supported by CBCRA, CIHR (MOP-89751) and Terry Fox team (020002) grants to WJM, a CIHR operating grant to JU-S (MOP-111143) and CIHR (MOP6849) and Terry Fox Foundation/CIHR (TFF105268) grants to TP JU-S is the recipient of a CIHR New Investigator Salary Support award. LP is supported by a CIHR/FRSQ training grant in cancer research of the McGill Integrated Cancer Research Training Program (MICRTP). WJM is supported by a CRC chair in molecular oncology. TP is a CIHR distinguished scientist.

Author information

Authors and Affiliations

  1. Lady Davis Institute for Medical Research, Montreal, Quebec, Canada

    J Ursini-Siegel & L Podmore

  2. University of Massachusetts Medical School, Worcester, MA, USA

    W R Hardy

  3. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

    Y Zheng, C Zhang & T Pawson

  4. Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada

    C Ling, D Zuo & W J Muller

Authors
  1. J Ursini-Siegel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W R Hardy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Ling
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L Podmore
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T Pawson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. W J Muller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Ursini-Siegel.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ursini-Siegel, J., Hardy, W., Zheng, Y. et al. The ShcA SH2 domain engages a 14-3-3/PI3′K signaling complex and promotes breast cancer cell survival. Oncogene 31, 5038–5044 (2012). https://doi.org/10.1038/onc.2012.4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2012.4

Keywords

This article is cited by

Search

Advanced search

Quick links