Abstract
Deregulated Her2/ErbB2 receptor tyrosine kinase drives tumorigenesis and tumor progression in a variety of human tissues. Her2 transmits oncogenic signals through phosphorylation of its cytosolic domain. To study innate cellular mechanisms for containing Her2 oncogenic phosphorylation, a siRNA phosphatase library was screened for cellular phosphatase(s) that enhance phosphorylation in the signaling motif of Her2 after knockdown. We found that silencing protein tyrosine phosphatase PTPN13 significantly augmented growth factor-induced phosphorylation of the Her2 signaling domain and promoted the invasiveness of Her2-deregulated cancer cells. In addition, we discovered that growth factor-induced phosphorylation of PTPN13 was essential for the dephosphorylation of Her2 suggesting a negative feedback mechanism induced by growth factor to inhibit cellular Her2 activity through PTPN13. Importantly, we showed that PTPN13 mutations previously reported in human tumors significantly reduced the phosphatase activity of PTPN13, and consequently elevated the oncogenic potential of Her2 and the invasiveness of Her2-overexpressing human cancer cells. Taken together, these results suggest that cellular PTPN13 inhibits Her2 activity by dephosphorylating the signal domain of Her2 and plays a role in attenuating invasiveness and metastasis of Her2 overactive tumors.
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References
Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A et al. (2004). Protein tyrosine phosphatases in the human genome. Cell 117: 699–711.
Bentires-Alj M, Neel BG . (2007). Protein-tyrosine phosphatase 1B is required for HER2/Neu-induced breast cancer. Cancer Res 67: 2420–2424.
Bompard G, Puech C, Prebois C, Vignon F, Freiss G . (2002). Protein-tyrosine phosphatase PTPL1/FAP-1 triggers apoptosis in human breast cancer cells. J Biol Chem 277: 47861–47869.
Cantin GT, Venable JD, Cociorva D, Yates III JR . (2006). Quantitative phosphoproteomic analysis of the tumor necrosis factor pathway. J Proteome Res 5: 127–134.
Engelman JA, Cantley LC . (2006). The role of the ErbB family members in non-small cell lung cancers sensitive to epidermal growth factor receptor kinase inhibitors. Clin Cancer Res 12: 4372s–4376s.
Erdmann KS . (2003). The protein tyrosine phosphatase PTP-Basophil/Basophil-like. Interacting proteins and molecular functions. Eur J Biochem 270: 4789–4798.
Gensler M, Buschbeck M, Ullrich A . (2004). Negative regulation of HER2 signaling by the PEST-type protein-tyrosine phosphatase BDP1. J Biol Chem 279: 12110–12116.
Gil-Henn H, Elson A . (2003). Tyrosine phosphatase-epsilon activates Src and supports the transformed phenotype of Neu-induced mammary tumor cells. J Biol Chem 278: 15579–15586.
Hackel PO, Zwick E, Prenzel N, Ullrich A . (1999). Epidermal growth factor receptors: critical mediators of multiple receptor pathways. Curr Opin Cell Biol 11: 184–189.
Haj FG, Markova B, Klaman LD, Bohmer FD, Neel BG . (2003). Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatase-1B. J Biol Chem 278: 739–744.
Hauck CR, Hsia DA, Puente XS, Cheresh DA, Schlaepfer DD . (2002). FRNK blocks v-Src-stimulated invasion and experimental metastases without effects on cell motility or growth. EMBO J 21: 6289–6302.
Hayes DF, Thor AD . (2002). c-erbB-2 in breast cancer: development of a clinically useful marker. Semin Oncol 29: 231–245.
Inazawa J, Ariyama T, Abe T, Druck T, Ohta M, Huebner K et al. (1996). PTPN13, a fas-associated protein tyrosine phosphatase, is located on the long arm of chromosome 4 at band q21.3. Genomics 31: 240–242.
Julien SG, Dube N, Read M, Penney J, Paquet M, Han Y et al. (2007). Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis. Nat Genet 39: 338–346.
Kato Y, Kravchenko VV, Tapping RI, Han J, Ulevitch RJ, Lee JD . (1997). BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C. EMBO J 16: 7054–7066.
Kim SW, Chao TH, Xiang R, Lo JF, Campbell MJ, Fearns C et al. (2004). Tid1, the human homologue of a Drosophila tumor suppressor, reduces the malignant activity of ErbB-2 in carcinoma cells. Cancer Res 64: 7732–7739.
Menard S, Casalini P, Campiglio M, Pupa SM, Tagliabue E . (2004). Role of HER2/neu in tumor progression and therapy. Cell Mol Life Sci 61: 2965–2978.
Moody SE, Sarkisian CJ, Hahn KT, Gunther EJ, Pickup S, Dugan KD et al. (2002). Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis. Cancer Cell 2: 451–461.
Ostman A, Hellberg C, Bohmer FD . (2006). Protein-tyrosine phosphatases and cancer. Nat Rev Cancer 6: 307–320.
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL . (1987). Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235: 177–182.
Tartaglia M, Gelb BD . (2005). Germ-line and somatic PTPN11 mutations in human disease. Eur J Med Genet 48: 81–96.
Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A et al. (2003). Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 34: 148–150.
Tonks NK . (2006). Protein tyrosine phosphatases: from genes, to function, to disease. Nat Rev Mol Cell Biol 7: 833–846.
Wang Z, Shen D, Parsons DW, Bardelli A, Sager J, Szabo S et al. (2004). Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science 304: 1164–1166.
Washburn MP, Wolters D, Yates III JR . (2001). Large-scale analysis of the yeast proteome by multidimensional protein identification technology. Nat Biotechnol 19: 242–247.
Xu Y, Tan LJ, Grachtchouk V, Voorhees JJ, Fisher GJ . (2005). Receptor-type protein-tyrosine phosphatase-kappa regulates epidermal growth factor receptor function. J Biol Chem 280: 42694–42700.
Yeh SH, Wu DC, Tsai CY, Kuo TJ, Yu WC, Chang YS et al. (2006). Genetic characterization of fas-associated phosphatase-1 as a putative tumor suppressor gene on chromosome 4q21.3 in hepatocellular carcinoma. Clin Cancer Res 12: 1097–1108.
Acknowledgements
This work was supported by funds from National Cancer Institute (CA079871 and CA114059), California Tobacco-Related Disease (15RT-0104) and Department of Defense BCRP (BC031105).
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
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Zhu, JH., Chen, R., Yi, W. et al. Protein tyrosine phosphatase PTPN13 negatively regulates Her2/ErbB2 malignant signaling. Oncogene 27, 2525–2531 (2008). https://doi.org/10.1038/sj.onc.1210922
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DOI: https://doi.org/10.1038/sj.onc.1210922
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