Cell Signaling

  • Daniel A. RappoleeEmail author
  • D. Randall Armant


Signal transduction is the molecular process whereby a cell receives, transmits, amplifies, and integrates extracellular stimuli. Key parameters of the signaling pathways are duration and magnitude of the input and subsequent biological responses. Key features of signaling processes include the time- and dose-dependent responses mediated by downstream molecular effectors. The precision of signaling is accomplished through negative feedback and branching between the pathways that mediate cross-talk. Since rate-limiting enzymes in different pathways have different inputs and outputs, integration of signal transduction pathways leads to the optimal biological responses that have been selected during evolution.


Signal transduction Pathway Communication cascade 


  1. Rappolee, D. (1998). Growth factors in the mammalian pre- and post-implantation embryo. Growth factors and hormones in mammalian development. In Hormones and Growth Factors in Development and Neoplasia., (ed. D. S. R Dickson), pp. 93–115. NYC: Wiley.Google Scholar
  2. Rappolee, D. and Werb, Z. (1994). The Role of Growth Factors in Early Mammalian development. Advances in Developmental Biology 3:41–71.CrossRefGoogle Scholar
  3. Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K. and Watson, J. D. (1994). Molecular biology of the cell. NY: Garland Publishing.Google Scholar
  4. Myers, M. G., Jr., Wang, L. M., Sun, X. J., Zhang, Y., Yenush, L., Schlessinger, J., Pierce, J. H. and White, M. F. (1994). Role of IRS-1-GRB-2 complexes in insulin signaling. Mol Cell Biol 14, 3577–3587.PubMedGoogle Scholar
  5. Angel, P. and Karin, M. (1991). The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta 1072, 129–157.Google Scholar
  6. Berridge, M. J., Lipp, P. and Bootman, M. D. (2000). The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 1, 11–21.Google Scholar
  7. Whitake, M. (2006). Calcium at fertilization and in early development. Physiol Rev 86, 25–88.Google Scholar
  8. Partanen, J., Vainikka, S., Korhonen, J., Armstrong, E. and Alitalo, K. (1992). Diverse receptors for fibroblast growth factors. Prog Growth Factor Res 4, 69–83.Google Scholar
  9. Hausdorff, W. P., Lohse, M. J., Bouvier, M., Liggett, S. B., Caron, M. G. and Lefkowitz, R. J. (1990). Two kinases mediate agonist-dependent phosphorylation and desensitization of the beta 2-adrenergic receptor. Symp Soc Exp Biol 44, 225–240.Google Scholar
  10. Hill, C. S. and Treisman, R. (1999). Growth factors and gene expression: fresh insights from arrays. Sci STKE 1999, PE1.Google Scholar
  11. Feramisco, J. R., Clark, R., Wong, G., Arnheim, N., Milley, R. and McCormick, F. (1985). Transient reversion of ras oncogene-induced cell transformation by antibodies specific for amino acid 12 of ras protein. Nature 314, 639–642.Google Scholar
  12. Jun, T., Gjoerup, O. and Roberts, T. M. (1999). Tangled webs: evidence of cross-talk between c-Raf-1 and Akt. Sci STKE 1999, PE1.Google Scholar
  13. Xie, Y., Zhang, W., Wang, Y., Trostinskaia, A., Wang, F., Puscheck, E. E. and Rappolee, D. A. (2007). Using hyperosmolar stress to measure biologic and stress-activated protein kinase responses in preimplantation embryos. Mol Hum Reprod 13, 473–481.Google Scholar
  14. Sun, H., Charles, C. H., Lau, L. F. and Tonks, N. K. (1993). MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Cell 75, 487–493.Google Scholar
  15. Mourey, R. J., Vega, Q. C., Campbell, J. S., Wenderoth, M. P., Hauschka, S. D., Krebs, E. G. and Dixon, J. E. (1996). A novel cytoplasmic dual specificity protein tyrosine phosphatase implicated in muscle and neuronal differentiation. J Biol Chem 271, 3795–3802.Google Scholar
  16. Shaw, G. and Kamen, R. (1986). A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 46, 659–667.Google Scholar
  17. Zhang, X., Ibrahimi, O. A., Olsen, S. K., Umemori, H., Mohammadi, M. and Ornitz, D. M. (2006a). Receptor specificity of the fibroblast growth factor family, part II. J Biol Chem.Google Scholar
  18. Zhang, X., Ibrahimi, O. A., Olsen, S. K., Umemori, H., Mohammadi, M. and Ornitz, D. M. (2006b). Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem 281, 15694–15700.Google Scholar
  19. Mohammadi, M., Dikic, I., Sorokin, A., Burgess, W. H., Jaye, M. and Schlessinger, J. (1996). Identification of six novel autophosphorylation sites on fibroblast growth factor receptor 1 and elucidation of their importance in receptor activation and signal transduction. Mol Cell Biol 16, 977–989.Google Scholar
  20. Tsang, M. and Dawid, I. B. (2004). Promotion and attenuation of FGF signaling through the Ras-MAPK pathway. Sci STKE 2004, pe17.Google Scholar
  21. Huang, J., Mohammadi, M., Rodrigues, G. A. and Schlessinger, J. (1995). Reduced activation of RAF-1 and MAP kinase by a fibroblast growth factor receptor mutant deficient in stimulation of phosphatidylinositol hydrolysis. J Biol Chem 270, 5065–5072.Google Scholar
  22. Dekker, L. V. and Parker, P. J. (1994). Protein kinase C—a question of specificity. Trends Biochem Sci 19, 73–77.Google Scholar
  23. Newton, A. C. (1997). Regulation of protein kinase. C. Curr Opin Cell Biol 9, 161–167.Google Scholar
  24. Lavoie, J. N., L'Allemain, G., Brunet, A., Muller, R. and Pouyssegur, J. (1996). Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J Biol Chem 271, 20608–20616.Google Scholar
  25. Mohammadi, M., Dionne, C. A., Li, W., Li, N., Spivak, T., Honegger, A. M., Jaye, M. and Schlessinger, J. (1992). Point mutation in FGF receptor eliminates phosphatidylinositol hydrolysis without affecting mitogenesis. Nature 358, 681–684.Google Scholar
  26. Peters, K. G., Marie, J., Wilson, E., Ives, H. E., Escobedo, J., Del Rosario, M., Mirda, D. and Williams, L. T. (1992). Point mutation of an FGF receptor abolishes phosphatidylinositol turnover and Ca++ flux but not mitogenesis. Nature 358, 678–681.Google Scholar
  27. Murakami, M. S. and Morrison, D. K. (2001). Raf-1 without MEK? Sci STKE 2001, PE30.Google Scholar
  28. Landgren, E., Blume-Jensen, P., Courtneidge, S. A. and Claesson-Welsh, L. (1995). Fibroblast growth factor receptor-1 regulation of Src family kinases. Oncogene 10, 2027–2035.Google Scholar
  29. Spivak-Kroizman, T., Mohammadi, M., Hu, P., Jaye, M., Schlessinger, J. and Lax, I. (1994). Point mutation in the fibroblast growth factor receptor eliminates phosphatidylinositol hydrolysis without affecting neuronal differentiation of PC12 cells. J Biol Chem 269, 14419–14423.Google Scholar
  30. Deng, C., Wynshaw-Boris, A., Zhou, F., Kuo, A. and Leder, P. (1996). Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 84, 911–921.Google Scholar
  31. Sahni, M., Ambrosetti, D. C., Mansukhani, A., Gertner, R., Levy, D. and Basilico, C. (1999). FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway. Genes Dev 13, 1361–1366.Google Scholar
  32. Shaulian, E. and Karin, M. (2002). AP-1 as a regulator of cell life and death. Nat Cell Biol 4, E131–6.Google Scholar
  33. Roovers, K. and Assoian, R. K. (2000). Integrating the MAP kinase signal into the G1 phase cell cycle machinery. Bioessays 22, 818–826.Google Scholar
  34. Chazaud, C., Yamanaka, Y., Pawson, T. and Rossant, J. (2006). Early Lineage Segregation between Epiblast and Primitive Endoderm in Mouse Blastocysts through the Grb2-MAPK Pathway. Dev Cell 10, 615–624.Google Scholar
  35. Kyriakis, J. M. and Avruch, J. (1996). Protein kinase cascades activated by stress and inflammatory cytokines. Bioessays 18, 567–577.Google Scholar
  36. Rappolee, D. A. (2007). Impact of transient stress and stress enzymes on development. Dev Biol 304, 1–8.Google Scholar
  37. Xie, Y., Liu, J., Proteasa, S., Proteasa, G., Zhong, W., Wang, Y., Wang, F., Puscheck, E. and Rappolee, D. (2008). Transient stress and stress enzyme responses have practical impacts on parameters of embryo development, from IVF to directed differentiation of stem cells. Mol Repro Dev,75, 689–697.Google Scholar
  38. Bhalla, U. S., Ram, P. T. and Iyengar, R. (2002). MAP kinase phosphatase as a locus of flexibility in a mitogen-activated protein kinase signaling network. Science 297, 1018–1023.Google Scholar
  39. Corson, L. B., Yamanaka, Y., Lai, K. M. and Rossant, J. (2003). Spatial and temporal patterns of ERK signaling during mouse embryogenesis. Development 130, 4527–4537.Google Scholar
  40. Wang, Y., Wang, F., Sun, T., Trostinskaia, A., Wygle, D., Puscheck, E. and Rappolee, D. A. (2004). Entire mitogen activated protein kinase (MAPK) pathway is present in preimplantation mouse embryos. Dev Dyn 231, 72–87.Google Scholar
  41. Harvey, M. B. and Kaye, P. L. (1991). Mouse blastocysts respond metabolically to short-term stimulation by insulin and IGF-1 through the insulin receptor. Mol Reprod Dev 29, 253–258.Google Scholar
  42. Dardik, A. and Schultz, R. M. (1991). Blastocoel expansion in the preimplantation mouse embryo: stimulatory effect of TGF-alpha and EGF. Development 113, 919–930.Google Scholar
  43. Mattson, B. A., Rosenblum, I. Y., Smith, R. M. and Heyner, S. (1988). Autoradiographic evidence for insulin and insulin-like growth factor binding to early mouse embryos. Diabetes 37, 585–589.Google Scholar
  44. Liu, Z. and Armant, D. R. (2004). Lysophosphatidic acid regulates murine blastocyst development by transactivation of receptors for heparin-binding EGF-like growth factor. Exp Cell Res 296, 317–326.Google Scholar
  45. Wang, J., Rout, U. K., Bagchi, I. C. and Armant, D. R. (1998). Expression of calcitonin receptors in mouse preimplantation embryos and their function in the regulation of blastocyst differentiation by calcitonin. Development 125, 4293–4302.Google Scholar
  46. Wang, J., Mayernik, L., Schultz, J. F. and Armant, D. R. (2000). Acceleration of trophoblast differentiation by heparin-binding EGF-like growth factor is dependent on the stage-specific activation of calcium influx by ErbB receptors in developing mouse blastocysts. Development 127, 33–44.Google Scholar
  47. Prenzel, N., Zwick, E., Daub, H., Leserer, M., Abraham, R., Wallasch, C. and Ullrich, A. (1999). EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402, 884–888.Google Scholar
  48. Schlessinger, J. (2004). Common and distinct elements in cellular signaling via EGF and FGF receptors. Science 306, 1506–1507.Google Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Wayne State University Medical School, Departments of Ob/Gyn and AnatomyDetroitUSA
  2. 2.Wayne State University School of MedicineDetroitUSA

Personalised recommendations