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. 1997 Sep;17(9):5328–5337. doi: 10.1128/mcb.17.9.5328

Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis.

Y E Chin 1, M Kitagawa 1, K Kuida 1, R A Flavell 1, X Y Fu 1
PMCID: PMC232383  PMID: 9271410

Abstract

Protein tyrosine kinases activate the STAT (signal transducer and activator of transcription) signaling pathway, which can play essential roles in cell differentiation, cell cycle control, and development. However, the potential role of the STAT signaling pathway in the induction of apoptosis remains unexplored. Here we show that gamma interferon (IFN-gamma) activated STAT1 and induced apoptosis in both A431 and HeLa cells, whereas epidermal growth factor (EGF) activated STAT proteins and induced apoptosis in A431 but not in HeLa cells. EGF receptor autophosphorylation and mitogen-activated protein kinase activation in response to EGF were similar in both cell lines. The breast cancer cell line MDA-MB-468 exhibited a similar response to A431 cells, i.e., STAT activation and apoptosis correlatively resulted from EGF or IFN-gamma treatment. In addition, in a mutant A431 cell line in which STAT activation was abolished, no apoptosis was induced by either EGF or IFN-gamma. We further demonstrated that both EGF and IFN-gamma induced caspase 1 (interleukin-1beta converting enzyme [ICE]) gene expression in a STAT-dependent manner. IFN-gamma was unable to induce ICE gene expression and apoptosis in either JAK1-deficient HeLa cells (E2A4) or STAT1-deficient cells (U3A). However, ICE gene expression and apoptosis were induced by IFN-gamma in U3A cells into which STAT1 had been reintroduced. Moreover, both EGF-induced apoptosis and IFN-gamma-induced apoptosis were effectively blocked by Z-Val-Ala-Asp-fluoromethylketone (ZVAD) in all the cells tested, and studies from ICE-deficient cells indicated that ICE gene expression was necessary for IFN-gamma-induced apoptosis. We conclude that activation of the STAT signaling pathway can induce apoptosis through the induction of ICE gene expression.

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Selected References

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  1. Alnemri E. S., Livingston D. J., Nicholson D. W., Salvesen G., Thornberry N. A., Wong W. W., Yuan J. Human ICE/CED-3 protease nomenclature. Cell. 1996 Oct 18;87(2):171–171. doi: 10.1016/s0092-8674(00)81334-3. [DOI] [PubMed] [Google Scholar]
  2. Armstrong D. K., Kaufmann S. H., Ottaviano Y. L., Furuya Y., Buckley J. A., Isaacs J. T., Davidson N. E. Epidermal growth factor-mediated apoptosis of MDA-MB-468 human breast cancer cells. Cancer Res. 1994 Oct 15;54(20):5280–5283. [PubMed] [Google Scholar]
  3. Beg A. A., Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science. 1996 Nov 1;274(5288):782–784. doi: 10.1126/science.274.5288.782. [DOI] [PubMed] [Google Scholar]
  4. Bennett M. R., Evan G. I., Newby A. C. Deregulated expression of the c-myc oncogene abolishes inhibition of proliferation of rat vascular smooth muscle cells by serum reduction, interferon-gamma, heparin, and cyclic nucleotide analogues and induces apoptosis. Circ Res. 1994 Mar;74(3):525–536. doi: 10.1161/01.res.74.3.525. [DOI] [PubMed] [Google Scholar]
  5. Boldin M. P., Goncharov T. M., Goltsev Y. V., Wallach D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell. 1996 Jun 14;85(6):803–815. doi: 10.1016/s0092-8674(00)81265-9. [DOI] [PubMed] [Google Scholar]
  6. Boudreau N., Sympson C. J., Werb Z., Bissell M. J. Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix. Science. 1995 Feb 10;267(5199):891–893. doi: 10.1126/science.7531366. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brabyn C. J., Kleine L. P. EGF causes hyperproliferation and apoptosis in T51B cells: involvement of high and low affinity EGFR binding sites. Cell Signal. 1995 Feb;7(2):139–150. doi: 10.1016/0898-6568(94)00073-k. [DOI] [PubMed] [Google Scholar]
  8. Buick R. N., Filmus J., Church J. G. The role of epidermal growth factor receptors in breast cancer. Cancer Treat Res. 1991;53:159–170. doi: 10.1007/978-1-4615-3940-7_7. [DOI] [PubMed] [Google Scholar]
  9. Cantley L. C., Auger K. R., Carpenter C., Duckworth B., Graziani A., Kapeller R., Soltoff S. Oncogenes and signal transduction. Cell. 1991 Jan 25;64(2):281–302. doi: 10.1016/0092-8674(91)90639-g. [DOI] [PubMed] [Google Scholar]
  10. Chin Y. E., Kitagawa M., Su W. C., You Z. H., Iwamoto Y., Fu X. Y. Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1. Science. 1996 May 3;272(5262):719–722. doi: 10.1126/science.272.5262.719. [DOI] [PubMed] [Google Scholar]
  11. Clarke A. R., Purdie C. A., Harrison D. J., Morris R. G., Bird C. C., Hooper M. L., Wyllie A. H. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature. 1993 Apr 29;362(6423):849–852. doi: 10.1038/362849a0. [DOI] [PubMed] [Google Scholar]
  12. Cleveland J. L., Ihle J. N. Contenders in FasL/TNF death signaling. Cell. 1995 May 19;81(4):479–482. doi: 10.1016/0092-8674(95)90068-3. [DOI] [PubMed] [Google Scholar]
  13. Darnell J. E., Jr, Kerr I. M., Stark G. R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994 Jun 3;264(5164):1415–1421. doi: 10.1126/science.8197455. [DOI] [PubMed] [Google Scholar]
  14. David M., Petricoin E., 3rd, Benjamin C., Pine R., Weber M. J., Larner A. C. Requirement for MAP kinase (ERK2) activity in interferon alpha- and interferon beta-stimulated gene expression through STAT proteins. Science. 1995 Sep 22;269(5231):1721–1723. doi: 10.1126/science.7569900. [DOI] [PubMed] [Google Scholar]
  15. Deiss L. P., Galinka H., Berissi H., Cohen O., Kimchi A. Cathepsin D protease mediates programmed cell death induced by interferon-gamma, Fas/APO-1 and TNF-alpha. EMBO J. 1996 Aug 1;15(15):3861–3870. [PMC free article] [PubMed] [Google Scholar]
  16. Dolle R. E., Hoyer D., Prasad C. V., Schmidt S. J., Helaszek C. T., Miller R. E., Ator M. A. P1 aspartate-based peptide alpha-((2,6-dichlorobenzoyl)oxy)methyl ketones as potent time-dependent inhibitors of interleukin-1 beta-converting enzyme. J Med Chem. 1994 Mar 4;37(5):563–564. doi: 10.1021/jm00031a003. [DOI] [PubMed] [Google Scholar]
  17. Ellis R. E., Yuan J. Y., Horvitz H. R. Mechanisms and functions of cell death. Annu Rev Cell Biol. 1991;7:663–698. doi: 10.1146/annurev.cb.07.110191.003311. [DOI] [PubMed] [Google Scholar]
  18. Enari M., Talanian R. V., Wong W. W., Nagata S. Sequential activation of ICE-like and CPP32-like proteases during Fas-mediated apoptosis. Nature. 1996 Apr 25;380(6576):723–726. doi: 10.1038/380723a0. [DOI] [PubMed] [Google Scholar]
  19. Englert C., Hou X., Maheswaran S., Bennett P., Ngwu C., Re G. G., Garvin A. J., Rosner M. R., Haber D. A. WT1 suppresses synthesis of the epidermal growth factor receptor and induces apoptosis. EMBO J. 1995 Oct 2;14(19):4662–4675. doi: 10.1002/j.1460-2075.1995.tb00148.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Filmus J., Pollak M. N., Cailleau R., Buick R. N. MDA-468, a human breast cancer cell line with a high number of epidermal growth factor (EGF) receptors, has an amplified EGF receptor gene and is growth inhibited by EGF. Biochem Biophys Res Commun. 1985 Apr 30;128(2):898–905. doi: 10.1016/0006-291x(85)90131-7. [DOI] [PubMed] [Google Scholar]
  21. Fraser A., Evan G. A license to kill. Cell. 1996 Jun 14;85(6):781–784. doi: 10.1016/s0092-8674(00)81005-3. [DOI] [PubMed] [Google Scholar]
  22. Fu X. Y. A transcription factor with SH2 and SH3 domains is directly activated by an interferon alpha-induced cytoplasmic protein tyrosine kinase(s). Cell. 1992 Jul 24;70(2):323–335. doi: 10.1016/0092-8674(92)90106-m. [DOI] [PubMed] [Google Scholar]
  23. Fu X. Y., Zhang J. J. Transcription factor p91 interacts with the epidermal growth factor receptor and mediates activation of the c-fos gene promoter. Cell. 1993 Sep 24;74(6):1135–1145. doi: 10.1016/0092-8674(93)90734-8. [DOI] [PubMed] [Google Scholar]
  24. Gill G. N., Lazar C. S. Increased phosphotyrosine content and inhibition of proliferation in EGF-treated A431 cells. Nature. 1981 Sep 24;293(5830):305–307. doi: 10.1038/293305a0. [DOI] [PubMed] [Google Scholar]
  25. Harrington E. A., Bennett M. R., Fanidi A., Evan G. I. c-Myc-induced apoptosis in fibroblasts is inhibited by specific cytokines. EMBO J. 1994 Jul 15;13(14):3286–3295. doi: 10.1002/j.1460-2075.1994.tb06630.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hsu H., Xiong J., Goeddel D. V. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell. 1995 May 19;81(4):495–504. doi: 10.1016/0092-8674(95)90070-5. [DOI] [PubMed] [Google Scholar]
  27. Ihle J. N., Kerr I. M. Jaks and Stats in signaling by the cytokine receptor superfamily. Trends Genet. 1995 Feb;11(2):69–74. doi: 10.1016/s0168-9525(00)89000-9. [DOI] [PubMed] [Google Scholar]
  28. Johnson M. D., Torri J. A., Lippman M. E., Dickson R. B. The role of cathepsin D in the invasiveness of human breast cancer cells. Cancer Res. 1993 Feb 15;53(4):873–877. [PubMed] [Google Scholar]
  29. Jung Y., Miura M., Yuan J. Suppression of interleukin-1 beta-converting enzyme-mediated cell death by insulin-like growth factor. J Biol Chem. 1996 Mar 1;271(9):5112–5117. doi: 10.1074/jbc.271.9.5112. [DOI] [PubMed] [Google Scholar]
  30. Juo P., Kuo C. J., Reynolds S. E., Konz R. F., Raingeaud J., Davis R. J., Biemann H. P., Blenis J. Fas activation of the p38 mitogen-activated protein kinase signalling pathway requires ICE/CED-3 family proteases. Mol Cell Biol. 1997 Jan;17(1):24–35. doi: 10.1128/mcb.17.1.24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Karin M., Hunter T. Transcriptional control by protein phosphorylation: signal transmission from the cell surface to the nucleus. Curr Biol. 1995 Jul 1;5(7):747–757. doi: 10.1016/s0960-9822(95)00151-5. [DOI] [PubMed] [Google Scholar]
  32. Karin M., Smeal T. Control of transcription factors by signal transduction pathways: the beginning of the end. Trends Biochem Sci. 1992 Oct;17(10):418–422. doi: 10.1016/0968-0004(92)90012-x. [DOI] [PubMed] [Google Scholar]
  33. Kawamoto T., Mendelsohn J., Le A., Sato G. H., Lazar C. S., Gill G. N. Relation of epidermal growth factor receptor concentration to growth of human epidermoid carcinoma A431 cells. J Biol Chem. 1984 Jun 25;259(12):7761–7766. [PubMed] [Google Scholar]
  34. Kim H. R., Upadhyay S., Li G., Palmer K. C., Deuel T. F. Platelet-derived growth factor induces apoptosis in growth-arrested murine fibroblasts. Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9500–9504. doi: 10.1073/pnas.92.21.9500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Kimchi A. Cytokine triggered molecular pathways that control cell cycle arrest. J Cell Biochem. 1992 Sep;50(1):1–9. doi: 10.1002/jcb.240500102. [DOI] [PubMed] [Google Scholar]
  36. Ko L. J., Prives C. p53: puzzle and paradigm. Genes Dev. 1996 May 1;10(9):1054–1072. doi: 10.1101/gad.10.9.1054. [DOI] [PubMed] [Google Scholar]
  37. Kuida K., Lippke J. A., Ku G., Harding M. W., Livingston D. J., Su M. S., Flavell R. A. Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. Science. 1995 Mar 31;267(5206):2000–2003. doi: 10.1126/science.7535475. [DOI] [PubMed] [Google Scholar]
  38. Larner A. C., David M., Feldman G. M., Igarashi K., Hackett R. H., Webb D. S., Sweitzer S. M., Petricoin E. F., 3rd, Finbloom D. S. Tyrosine phosphorylation of DNA binding proteins by multiple cytokines. Science. 1993 Sep 24;261(5129):1730–1733. doi: 10.1126/science.8378773. [DOI] [PubMed] [Google Scholar]
  39. Liu Z. G., Hsu H., Goeddel D. V., Karin M. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Cell. 1996 Nov 1;87(3):565–576. doi: 10.1016/s0092-8674(00)81375-6. [DOI] [PubMed] [Google Scholar]
  40. Loh J. E., Schindler C., Ziemiecki A., Harpur A. G., Wilks A. F., Flavell R. A. Mutant cell lines unresponsive to alpha/beta and gamma interferon are defective in tyrosine phosphorylation of ISGF-3 alpha components. Mol Cell Biol. 1994 Mar;14(3):2170–2179. doi: 10.1128/mcb.14.3.2170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Martin S. J., Green D. R. Protease activation during apoptosis: death by a thousand cuts? Cell. 1995 Aug 11;82(3):349–352. doi: 10.1016/0092-8674(95)90422-0. [DOI] [PubMed] [Google Scholar]
  42. McKendry R., John J., Flavell D., Müller M., Kerr I. M., Stark G. R. High-frequency mutagenesis of human cells and characterization of a mutant unresponsive to both alpha and gamma interferons. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11455–11459. doi: 10.1073/pnas.88.24.11455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Minami M., Inoue M., Wei S., Takeda K., Matsumoto M., Kishimoto T., Akira S. STAT3 activation is a critical step in gp130-mediated terminal differentiation and growth arrest of a myeloid cell line. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):3963–3966. doi: 10.1073/pnas.93.9.3963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Miura M., Zhu H., Rotello R., Hartwieg E. A., Yuan J. Induction of apoptosis in fibroblasts by IL-1 beta-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. Cell. 1993 Nov 19;75(4):653–660. doi: 10.1016/0092-8674(93)90486-a. [DOI] [PubMed] [Google Scholar]
  45. Muzio M., Chinnaiyan A. M., Kischkel F. C., O'Rourke K., Shevchenko A., Ni J., Scaffidi C., Bretz J. D., Zhang M., Gentz R. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex. Cell. 1996 Jun 14;85(6):817–827. doi: 10.1016/s0092-8674(00)81266-0. [DOI] [PubMed] [Google Scholar]
  46. Müller M., Briscoe J., Laxton C., Guschin D., Ziemiecki A., Silvennoinen O., Harpur A. G., Barbieri G., Witthuhn B. A., Schindler C. The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction. Nature. 1993 Nov 11;366(6451):129–135. doi: 10.1038/366129a0. [DOI] [PubMed] [Google Scholar]
  47. Oberhammer F. A., Pavelka M., Sharma S., Tiefenbacher R., Purchio A. F., Bursch W., Schulte-Hermann R. Induction of apoptosis in cultured hepatocytes and in regressing liver by transforming growth factor beta 1. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5408–5412. doi: 10.1073/pnas.89.12.5408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Park O. K., Schaefer T. S., Nathans D. In vitro activation of Stat3 by epidermal growth factor receptor kinase. Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13704–13708. doi: 10.1073/pnas.93.24.13704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Pawson T. SH2 and SH3 domains in signal transduction. Adv Cancer Res. 1994;64:87–110. doi: 10.1016/s0065-230x(08)60835-0. [DOI] [PubMed] [Google Scholar]
  50. Quelle F. W., Thierfelder W., Witthuhn B. A., Tang B., Cohen S., Ihle J. N. Phosphorylation and activation of the DNA binding activity of purified Stat1 by the Janus protein-tyrosine kinases and the epidermal growth factor receptor. J Biol Chem. 1995 Sep 1;270(35):20775–20780. doi: 10.1074/jbc.270.35.20775. [DOI] [PubMed] [Google Scholar]
  51. Raff M. C. Social controls on cell survival and cell death. Nature. 1992 Apr 2;356(6368):397–400. doi: 10.1038/356397a0. [DOI] [PubMed] [Google Scholar]
  52. Schindler C., Shuai K., Prezioso V. R., Darnell J. E., Jr Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science. 1992 Aug 7;257(5071):809–813. doi: 10.1126/science.1496401. [DOI] [PubMed] [Google Scholar]
  53. Schlessinger J., Ullrich A. Growth factor signaling by receptor tyrosine kinases. Neuron. 1992 Sep;9(3):383–391. doi: 10.1016/0896-6273(92)90177-f. [DOI] [PubMed] [Google Scholar]
  54. Shi L., Chen G., MacDonald G., Bergeron L., Li H., Miura M., Rotello R. J., Miller D. K., Li P., Seshadri T. Activation of an interleukin 1 converting enzyme-dependent apoptosis pathway by granzyme B. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11002–11007. doi: 10.1073/pnas.93.20.11002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Shuai K., Stark G. R., Kerr I. M., Darnell J. E., Jr A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma. Science. 1993 Sep 24;261(5129):1744–1746. doi: 10.1126/science.7690989. [DOI] [PubMed] [Google Scholar]
  56. Sporn M. B., Roberts A. B. Peptide growth factors are multifunctional. Nature. 1988 Mar 17;332(6161):217–219. doi: 10.1038/332217a0. [DOI] [PubMed] [Google Scholar]
  57. Steller H. Mechanisms and genes of cellular suicide. Science. 1995 Mar 10;267(5203):1445–1449. doi: 10.1126/science.7878463. [DOI] [PubMed] [Google Scholar]
  58. Su W. C., Kitagawa M., Xue N., Xie B., Garofalo S., Cho J., Deng C., Horton W. A., Fu X. Y. Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. Nature. 1997 Mar 20;386(6622):288–292. doi: 10.1038/386288a0. [DOI] [PubMed] [Google Scholar]
  59. Tamura T., Ishihara M., Lamphier M. S., Tanaka N., Oishi I., Aizawa S., Matsuyama T., Mak T. W., Taki S., Taniguchi T. An IRF-1-dependent pathway of DNA damage-induced apoptosis in mitogen-activated T lymphocytes. Nature. 1995 Aug 17;376(6541):596–599. doi: 10.1038/376596a0. [DOI] [PubMed] [Google Scholar]
  60. Tartaglia L. A., Ayres T. M., Wong G. H., Goeddel D. V. A novel domain within the 55 kd TNF receptor signals cell death. Cell. 1993 Sep 10;74(5):845–853. doi: 10.1016/0092-8674(93)90464-2. [DOI] [PubMed] [Google Scholar]
  61. Tewari M., Quan L. T., O'Rourke K., Desnoyers S., Zeng Z., Beidler D. R., Poirier G. G., Salvesen G. S., Dixit V. M. Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell. 1995 Jun 2;81(5):801–809. doi: 10.1016/0092-8674(95)90541-3. [DOI] [PubMed] [Google Scholar]
  62. Thompson C. B. Apoptosis in the pathogenesis and treatment of disease. Science. 1995 Mar 10;267(5203):1456–1462. doi: 10.1126/science.7878464. [DOI] [PubMed] [Google Scholar]
  63. Tsujii M., DuBois R. N. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell. 1995 Nov 3;83(3):493–501. doi: 10.1016/0092-8674(95)90127-2. [DOI] [PubMed] [Google Scholar]
  64. Velazquez L., Fellous M., Stark G. R., Pellegrini S. A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Cell. 1992 Jul 24;70(2):313–322. doi: 10.1016/0092-8674(92)90105-l. [DOI] [PubMed] [Google Scholar]
  65. White E. Life, death, and the pursuit of apoptosis. Genes Dev. 1996 Jan 1;10(1):1–15. doi: 10.1101/gad.10.1.1. [DOI] [PubMed] [Google Scholar]
  66. Wyllie A. H., Kerr J. F., Currie A. R. Cell death: the significance of apoptosis. Int Rev Cytol. 1980;68:251–306. doi: 10.1016/s0074-7696(08)62312-8. [DOI] [PubMed] [Google Scholar]
  67. Xia K., Mukhopadhyay N. K., Inhorn R. C., Barber D. L., Rose P. E., Lee R. S., Narsimhan R. P., D'Andrea A. D., Griffin J. D., Roberts T. M. The cytokine-activated tyrosine kinase JAK2 activates Raf-1 in a p21ras-dependent manner. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11681–11686. doi: 10.1073/pnas.93.21.11681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Yuan J., Shaham S., Ledoux S., Ellis H. M., Horvitz H. R. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell. 1993 Nov 19;75(4):641–652. doi: 10.1016/0092-8674(93)90485-9. [DOI] [PubMed] [Google Scholar]
  69. Zhong Z., Wen Z., Darnell J. E., Jr Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994 Apr 1;264(5155):95–98. doi: 10.1126/science.8140422. [DOI] [PubMed] [Google Scholar]
  70. van der Geer P., Hunter T., Lindberg R. A. Receptor protein-tyrosine kinases and their signal transduction pathways. Annu Rev Cell Biol. 1994;10:251–337. doi: 10.1146/annurev.cb.10.110194.001343. [DOI] [PubMed] [Google Scholar]

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