Skip to main content
PMC home page
Biophysical Journal logoLink to Biophysical Journal
. 2002 Feb;82(2):591–604. doi: 10.1016/S0006-3495(02)75424-6

A unified model for signal transduction reactions in cellular membranes.

Jason M Haugh 1
PMCID: PMC1301871  PMID: 11806904

Abstract

An analytical solution is obtained for the steady-state reaction rate of an intracellular enzyme, recruited to the plasma membrane by active receptors, acting upon a membrane-associated substrate. Influenced by physical and chemical effects, such interactions are encountered in numerous signal-transduction pathways. The generalized modeling framework is the first to combine reaction and diffusion limitations in enzyme action, the finite mean lifetime of receptor-enzyme complexes, reactions in the bulk membrane, and constitutive and receptor-mediated substrate insertion. The theory is compared with other analytical and numerical approaches, and it is used to model two different signaling pathway types. For two-state mechanisms, such as activation of the Ras GTPase, the diffusion-limited activation rate constant increases with enhanced substrate inactivation, dissociation of receptor-enzyme complexes, or crowding of neighboring complexes. The latter effect is only significant when nearly all of the substrate is in the activated state. For regulated supply and turnover pathways, such as phospholipase C-mediated lipid hydrolysis, an additional influence is receptor-mediated substrate delivery. When substrate consumption is rapid, this process significantly enhances the effective enzymatic rate constant, regardless of whether enzyme action is diffusion limited. Under these conditions, however, enhanced substrate delivery can result in a decrease in the average substrate concentration.

Full Text

The Full Text of this article is available as a PDF (259.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aronheim A., Engelberg D., Li N., al-Alawi N., Schlessinger J., Karin M. Membrane targeting of the nucleotide exchange factor Sos is sufficient for activating the Ras signaling pathway. Cell. 1994 Sep 23;78(6):949–961. doi: 10.1016/0092-8674(94)90271-2. [DOI] [PubMed] [Google Scholar]
  2. Asthagiri A. R., Lauffenburger D. A. Bioengineering models of cell signaling. Annu Rev Biomed Eng. 2000;2:31–53. doi: 10.1146/annurev.bioeng.2.1.31. [DOI] [PubMed] [Google Scholar]
  3. Batty I. H., Currie R. A., Downes C. P. Evidence for a model of integrated inositol phospholipid pools implies an essential role for lipid transport in the maintenance of receptor-mediated phospholipase C activity in 1321N1 cells. Biochem J. 1998 Mar 15;330(Pt 3):1069–1077. doi: 10.1042/bj3301069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berg H. C., Purcell E. M. Physics of chemoreception. Biophys J. 1977 Nov;20(2):193–219. doi: 10.1016/S0006-3495(77)85544-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Buday L., Downward J. Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Cell. 1993 May 7;73(3):611–620. doi: 10.1016/0092-8674(93)90146-h. [DOI] [PubMed] [Google Scholar]
  6. Feder T. J., Brust-Mascher I., Slattery J. P., Baird B., Webb W. W. Constrained diffusion or immobile fraction on cell surfaces: a new interpretation. Biophys J. 1996 Jun;70(6):2767–2773. doi: 10.1016/S0006-3495(96)79846-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Goldstein B., Wofsy C., Echavarría-Heras H. Effect of membrane flow on the capture of receptors by coated pits. Theoretical results. Biophys J. 1988 Mar;53(3):405–414. doi: 10.1016/S0006-3495(88)83117-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hamm H. E., Gilchrist A. Heterotrimeric G proteins. Curr Opin Cell Biol. 1996 Apr;8(2):189–196. doi: 10.1016/s0955-0674(96)80065-2. [DOI] [PubMed] [Google Scholar]
  9. Haugh J. M., Lauffenburger D. A. Analysis of receptor internalization as a mechanism for modulating signal transduction. J Theor Biol. 1998 Nov 21;195(2):187–218. doi: 10.1006/jtbi.1998.0791. [DOI] [PubMed] [Google Scholar]
  10. Haugh J. M., Lauffenburger D. A. Physical modulation of intracellular signaling processes by locational regulation. Biophys J. 1997 May;72(5):2014–2031. doi: 10.1016/S0006-3495(97)78846-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Haugh J. M., Schooler K., Wells A., Wiley H. S., Lauffenburger D. A. Effect of epidermal growth factor receptor internalization on regulation of the phospholipase C-gamma1 signaling pathway. J Biol Chem. 1999 Mar 26;274(13):8958–8965. doi: 10.1074/jbc.274.13.8958. [DOI] [PubMed] [Google Scholar]
  12. Haugh J. M., Wells A., Lauffenburger D. A. Mathematical modeling of epidermal growth factor receptor signaling through the phospholipase C pathway: mechanistic insights and predictions for molecular interventions. Biotechnol Bioeng. 2000 Oct 20;70(2):225–238. [PubMed] [Google Scholar]
  13. Hsuan J. J., Tan S. H. Growth factor-dependent phosphoinositide signalling. Int J Biochem Cell Biol. 1997 Mar;29(3):415–435. doi: 10.1016/s1357-2725(96)00163-x. [DOI] [PubMed] [Google Scholar]
  14. Kauffmann-Zeh A., Klinger R., Endemann G., Waterfield M. D., Wetzker R., Hsuan J. J. Regulation of human type II phosphatidylinositol kinase activity by epidermal growth factor-dependent phosphorylation and receptor association. J Biol Chem. 1994 Dec 9;269(49):31243–31251. [PubMed] [Google Scholar]
  15. Kauffmann-Zeh A., Thomas G. M., Ball A., Prosser S., Cunningham E., Cockcroft S., Hsuan J. J. Requirement for phosphatidylinositol transfer protein in epidermal growth factor signaling. Science. 1995 May 26;268(5214):1188–1190. doi: 10.1126/science.7761838. [DOI] [PubMed] [Google Scholar]
  16. Keizer J., Ramirez J., Peacock-López E. The effect of diffusion on the binding of membrane-bound receptors to coated pits. Biophys J. 1985 Jan;47(1):79–87. doi: 10.1016/S0006-3495(85)83879-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kholodenko B. N., Hoek J. B., Westerhoff H. V. Why cytoplasmic signalling proteins should be recruited to cell membranes. Trends Cell Biol. 2000 May;10(5):173–178. doi: 10.1016/s0962-8924(00)01741-4. [DOI] [PubMed] [Google Scholar]
  18. Klippel A., Reinhard C., Kavanaugh W. M., Apell G., Escobedo M. A., Williams L. T. Membrane localization of phosphatidylinositol 3-kinase is sufficient to activate multiple signal-transducing kinase pathways. Mol Cell Biol. 1996 Aug;16(8):4117–4127. doi: 10.1128/mcb.16.8.4117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lenzen C., Cool R. H., Prinz H., Kuhlmann J., Wittinghofer A. Kinetic analysis by fluorescence of the interaction between Ras and the catalytic domain of the guanine nucleotide exchange factor Cdc25Mm. Biochemistry. 1998 May 19;37(20):7420–7430. doi: 10.1021/bi972621j. [DOI] [PubMed] [Google Scholar]
  20. Mahama P. A., Linderman J. J. A Monte Carlo study of the dynamics of G-protein activation. Biophys J. 1994 Sep;67(3):1345–1357. doi: 10.1016/S0006-3495(94)80606-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Medema R. H., de Vries-Smits A. M., van der Zon G. C., Maassen J. A., Bos J. L. Ras activation by insulin and epidermal growth factor through enhanced exchange of guanine nucleotides on p21ras. Mol Cell Biol. 1993 Jan;13(1):155–162. doi: 10.1128/mcb.13.1.155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Mineo C., James G. L., Smart E. J., Anderson R. G. Localization of epidermal growth factor-stimulated Ras/Raf-1 interaction to caveolae membrane. J Biol Chem. 1996 May 17;271(20):11930–11935. doi: 10.1074/jbc.271.20.11930. [DOI] [PubMed] [Google Scholar]
  23. Niv H., Gutman O., Henis Y. I., Kloog Y. Membrane interactions of a constitutively active GFP-Ki-Ras 4B and their role in signaling. Evidence from lateral mobility studies. J Biol Chem. 1999 Jan 15;274(3):1606–1613. doi: 10.1074/jbc.274.3.1606. [DOI] [PubMed] [Google Scholar]
  24. Pawson T. Protein modules and signalling networks. Nature. 1995 Feb 16;373(6515):573–580. doi: 10.1038/373573a0. [DOI] [PubMed] [Google Scholar]
  25. Pike L. J., Casey L. Localization and turnover of phosphatidylinositol 4,5-bisphosphate in caveolin-enriched membrane domains. J Biol Chem. 1996 Oct 25;271(43):26453–26456. doi: 10.1074/jbc.271.43.26453. [DOI] [PubMed] [Google Scholar]
  26. Pralle A., Keller P., Florin E. L., Simons K., Hörber J. K. Sphingolipid-cholesterol rafts diffuse as small entities in the plasma membrane of mammalian cells. J Cell Biol. 2000 Mar 6;148(5):997–1008. doi: 10.1083/jcb.148.5.997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Quilliam L. A., Huff S. Y., Rabun K. M., Wei W., Park W., Broek D., Der C. J. Membrane-targeting potentiates guanine nucleotide exchange factor CDC25 and SOS1 activation of Ras transforming activity. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8512–8516. doi: 10.1073/pnas.91.18.8512. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rameh L. E., Cantley L. C. The role of phosphoinositide 3-kinase lipid products in cell function. J Biol Chem. 1999 Mar 26;274(13):8347–8350. doi: 10.1074/jbc.274.13.8347. [DOI] [PubMed] [Google Scholar]
  29. Rhee S. G., Bae Y. S. Regulation of phosphoinositide-specific phospholipase C isozymes. J Biol Chem. 1997 Jun 13;272(24):15045–15048. doi: 10.1074/jbc.272.24.15045. [DOI] [PubMed] [Google Scholar]
  30. Schlessinger J., Axelrod D., Koppel D. E., Webb W. W., Elson E. L. Lateral transport of a lipid probe and labeled proteins on a cell membrane. Science. 1977 Jan 21;195(4275):307–309. doi: 10.1126/science.556653. [DOI] [PubMed] [Google Scholar]
  31. Shea L. D., Omann G. M., Linderman J. J. Calculation of diffusion-limited kinetics for the reactions in collision coupling and receptor cross-linking. Biophys J. 1997 Dec;73(6):2949–2959. doi: 10.1016/S0006-3495(97)78323-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sheetz M. P. Glycoprotein motility and dynamic domains in fluid plasma membranes. Annu Rev Biophys Biomol Struct. 1993;22:417–431. doi: 10.1146/annurev.bb.22.060193.002221. [DOI] [PubMed] [Google Scholar]
  33. Toker A. The synthesis and cellular roles of phosphatidylinositol 4,5-bisphosphate. Curr Opin Cell Biol. 1998 Apr;10(2):254–261. doi: 10.1016/s0955-0674(98)80148-8. [DOI] [PubMed] [Google Scholar]
  34. Tolkovsky A. M., Levitzki A. Mode of coupling between the beta-adrenergic receptor and adenylate cyclase in turkey erythrocytes. Biochemistry. 1978 Sep 5;17(18):3795–3795. doi: 10.1021/bi00611a020. [DOI] [PubMed] [Google Scholar]
  35. Vanhaesebroeck B., Waterfield M. D. Signaling by distinct classes of phosphoinositide 3-kinases. Exp Cell Res. 1999 Nov 25;253(1):239–254. doi: 10.1006/excr.1999.4701. [DOI] [PubMed] [Google Scholar]
  36. Weng G., Bhalla U. S., Iyengar R. Complexity in biological signaling systems. Science. 1999 Apr 2;284(5411):92–96. doi: 10.1126/science.284.5411.92. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Wiegel F. W., DeLisi C. Evaluation of reaction rate enhancement by reduction in dimensionality. Am J Physiol. 1982 Nov;243(5):R475–R479. doi: 10.1152/ajpregu.1982.243.5.R475. [DOI] [PubMed] [Google Scholar]
  38. Willars G. B., Nahorski S. R., Challiss R. A. Differential regulation of muscarinic acetylcholine receptor-sensitive polyphosphoinositide pools and consequences for signaling in human neuroblastoma cells. J Biol Chem. 1998 Feb 27;273(9):5037–5046. doi: 10.1074/jbc.273.9.5037. [DOI] [PubMed] [Google Scholar]
  39. Wittinghofer A., Scheffzek K., Ahmadian M. R. The interaction of Ras with GTPase-activating proteins. FEBS Lett. 1997 Jun 23;410(1):63–67. doi: 10.1016/s0014-5793(97)00321-9. [DOI] [PubMed] [Google Scholar]
  40. Wittinghofer A. Signal transduction via Ras. Biol Chem. 1998 Aug-Sep;379(8-9):933–937. [PubMed] [Google Scholar]
  41. 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]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES