Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1993 Apr;12(4):1681–1692. doi: 10.1002/j.1460-2075.1993.tb05813.x

Mechanical stretch rapidly activates multiple signal transduction pathways in cardiac myocytes: potential involvement of an autocrine/paracrine mechanism.

J Sadoshima 1, S Izumo 1
PMCID: PMC413382  PMID: 8385610

Abstract

It is well known that external load plays a critical role in determining cardiac muscle mass and its phenotype, but little is known as to how mechanical load is transduced into intracellular signals regulating gene expression. To address this question we analyzed the 'mechano-transcription' coupling process using an in vitro model of load-induced cardiac hypertrophy, in which a stretch of rat cardiac myocytes, grown on a deformable substrate, causes a rapid induction of immediate-early genes followed by growth (hypertrophic) response. We report here that cell stretch rapidly activates a plethora of second messenger pathways, including tyrosine kinases, p21ras, mitogen-activated protein (MAP) kinases, S6 kinases (pp90RSK), protein kinase C, phospholipase C, phospholipase D, and probably the phospholipase A2 and P450 pathways. In contrast, the cAMP pathway is not activated significantly by stretch. The signals generated by these second messengers appear to converge into activation of the p67SRF-p62TCF complex via the serum response element, causing induction of c-fos. The stretch response may involve an autocrine or paracrine mechanism, because stretch-conditioned medium, when transferred to non-stretched myocytes, mimicked the effect of stretch. These results indicate that mechanical load causes rapid activation of multiple second messenger systems, which may in turn initiate a cascade of hypertrophic response of cardiac myocytes.

Full text

PDF
1681

Images in this article

1682Image
on p.1682
1683Image
on p.1683
1685Image
on p.1685
1686Image
on p.1686
1687Image
on p.1687
1688Image
on p.1688
1689Image
on p.1689
1689Image
on p.1689

Selected References

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

  1. Akiyama T., Ishida J., Nakagawa S., Ogawara H., Watanabe S., Itoh N., Shibuya M., Fukami Y. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem. 1987 Apr 25;262(12):5592–5595. [PubMed] [Google Scholar]
  2. Alexander D. R., Graves J. D., Lucas S. C., Cantrell D. A., Crumpton M. J. A method for measuring protein kinase C activity in permeabilized T lymphocytes by using peptide substrates. Evidence for multiple pathways of kinase activation. Biochem J. 1990 Jun 1;268(2):303–308. doi: 10.1042/bj2680303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Axelrod J. Receptor-mediated activation of phospholipase A2 and arachidonic acid release in signal transduction. Biochem Soc Trans. 1990 Aug;18(4):503–507. doi: 10.1042/bst0180503. [DOI] [PubMed] [Google Scholar]
  4. BLIGH E. G., DYER W. J. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959 Aug;37(8):911–917. doi: 10.1139/o59-099. [DOI] [PubMed] [Google Scholar]
  5. Bader D., Masaki T., Fischman D. A. Immunochemical analysis of myosin heavy chain during avian myogenesis in vivo and in vitro. J Cell Biol. 1982 Dec;95(3):763–770. doi: 10.1083/jcb.95.3.763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Berkowitz L. A., Riabowol K. T., Gilman M. Z. Multiple sequence elements of a single functional class are required for cyclic AMP responsiveness of the mouse c-fos promoter. Mol Cell Biol. 1989 Oct;9(10):4272–4281. doi: 10.1128/mcb.9.10.4272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Berridge M. J., Heslop J. P., Irvine R. F., Brown K. D. Inositol trisphosphate formation and calcium mobilization in Swiss 3T3 cells in response to platelet-derived growth factor. Biochem J. 1984 Aug 15;222(1):195–201. doi: 10.1042/bj2220195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bishop J. M. Molecular themes in oncogenesis. Cell. 1991 Jan 25;64(2):235–248. doi: 10.1016/0092-8674(91)90636-d. [DOI] [PubMed] [Google Scholar]
  9. Blenis J. Growth-regulated signal transduction by the MAP kinases and RSKs. Cancer Cells. 1991 Nov;3(11):445–449. [PubMed] [Google Scholar]
  10. 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]
  11. Chen R. H., Chung J., Blenis J. Regulation of pp90rsk phosphorylation and S6 phosphotransferase activity in Swiss 3T3 cells by growth factor-, phorbol ester-, and cyclic AMP-mediated signal transduction. Mol Cell Biol. 1991 Apr;11(4):1861–1867. doi: 10.1128/mcb.11.4.1861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Chen R. H., Sarnecki C., Blenis J. Nuclear localization and regulation of erk- and rsk-encoded protein kinases. Mol Cell Biol. 1992 Mar;12(3):915–927. doi: 10.1128/mcb.12.3.915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Chien K. R., Knowlton K. U., Zhu H., Chien S. Regulation of cardiac gene expression during myocardial growth and hypertrophy: molecular studies of an adaptive physiologic response. FASEB J. 1991 Dec;5(15):3037–3046. doi: 10.1096/fasebj.5.15.1835945. [DOI] [PubMed] [Google Scholar]
  14. Christy B., Nathans D. Functional serum response elements upstream of the growth factor-inducible gene zif268. Mol Cell Biol. 1989 Nov;9(11):4889–4895. doi: 10.1128/mcb.9.11.4889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Cobb M. H., Robbins D. J., Boulton T. G. ERKs, extracellular signal-regulated MAP-2 kinases. Curr Opin Cell Biol. 1991 Dec;3(6):1025–1032. doi: 10.1016/0955-0674(91)90124-h. [DOI] [PubMed] [Google Scholar]
  16. Cockcroft S., Gomperts B. D. Role of guanine nucleotide binding protein in the activation of polyphosphoinositide phosphodiesterase. Nature. 1985 Apr 11;314(6011):534–536. doi: 10.1038/314534a0. [DOI] [PubMed] [Google Scholar]
  17. Dennis E. A., Rhee S. G., Billah M. M., Hannun Y. A. Role of phospholipase in generating lipid second messengers in signal transduction. FASEB J. 1991 Apr;5(7):2068–2077. doi: 10.1096/fasebj.5.7.1901288. [DOI] [PubMed] [Google Scholar]
  18. Downward J., Graves J. D., Warne P. H., Rayter S., Cantrell D. A. Stimulation of p21ras upon T-cell activation. Nature. 1990 Aug 23;346(6286):719–723. doi: 10.1038/346719a0. [DOI] [PubMed] [Google Scholar]
  19. Erikson R. L. Structure, expression, and regulation of protein kinases involved in the phosphorylation of ribosomal protein S6. J Biol Chem. 1991 Apr 5;266(10):6007–6010. [PubMed] [Google Scholar]
  20. Exton J. H. Signaling through phosphatidylcholine breakdown. J Biol Chem. 1990 Jan 5;265(1):1–4. [PubMed] [Google Scholar]
  21. Ferguson J. E., Hanley M. R. The role of phospholipases and phospholipid-derived signals in cell activation. Curr Opin Cell Biol. 1991 Apr;3(2):206–212. doi: 10.1016/0955-0674(91)90140-t. [DOI] [PubMed] [Google Scholar]
  22. Geiger R. V., Berk B. C., Alexander R. W., Nerem R. M. Flow-induced calcium transients in single endothelial cells: spatial and temporal analysis. Am J Physiol. 1992 Jun;262(6 Pt 1):C1411–C1417. doi: 10.1152/ajpcell.1992.262.6.C1411. [DOI] [PubMed] [Google Scholar]
  23. Gille H., Sharrocks A. D., Shaw P. E. Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter. Nature. 1992 Jul 30;358(6385):414–417. doi: 10.1038/358414a0. [DOI] [PubMed] [Google Scholar]
  24. Gilman M. Z. The c-fos serum response element responds to protein kinase C-dependent and -independent signals but not to cyclic AMP. Genes Dev. 1988 Apr;2(4):394–402. doi: 10.1101/gad.2.4.394. [DOI] [PubMed] [Google Scholar]
  25. Gotoh Y., Nishida E., Sakai H. Okadaic acid activates microtubule-associated protein kinase in quiescent fibroblastic cells. Eur J Biochem. 1990 Nov 13;193(3):671–674. doi: 10.1111/j.1432-1033.1990.tb19385.x. [DOI] [PubMed] [Google Scholar]
  26. Graham R., Gilman M. Distinct protein targets for signals acting at the c-fos serum response element. Science. 1991 Jan 11;251(4990):189–192. doi: 10.1126/science.1898992. [DOI] [PubMed] [Google Scholar]
  27. Grueneberg D. A., Natesan S., Alexandre C., Gilman M. Z. Human and Drosophila homeodomain proteins that enhance the DNA-binding activity of serum response factor. Science. 1992 Aug 21;257(5073):1089–1095. doi: 10.1126/science.257.5073.1089. [DOI] [PubMed] [Google Scholar]
  28. Haliday E. M., Ramesha C. S., Ringold G. TNF induces c-fos via a novel pathway requiring conversion of arachidonic acid to a lipoxygenase metabolite. EMBO J. 1991 Jan;10(1):109–115. doi: 10.1002/j.1460-2075.1991.tb07926.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Hammond G. L., Lai Y. K., Markert C. L. The molecules that initiate cardiac hypertrophy are not species-specific. Science. 1982 Apr 30;216(4545):529–531. doi: 10.1126/science.6461921. [DOI] [PubMed] [Google Scholar]
  30. Hannun Y. A., Merrill A. H., Jr, Bell R. M. Use of sphingosine as inhibitor of protein kinase C. Methods Enzymol. 1991;201:316–328. doi: 10.1016/0076-6879(91)01028-z. [DOI] [PubMed] [Google Scholar]
  31. Henrich C. J., Simpson P. C. Differential acute and chronic response of protein kinase C in cultured neonatal rat heart myocytes to alpha 1-adrenergic and phorbol ester stimulation. J Mol Cell Cardiol. 1988 Dec;20(12):1081–1085. doi: 10.1016/0022-2828(88)90588-3. [DOI] [PubMed] [Google Scholar]
  32. Holt J. T., Gopal T. V., Moulton A. D., Nienhuis A. W. Inducible production of c-fos antisense RNA inhibits 3T3 cell proliferation. Proc Natl Acad Sci U S A. 1986 Jul;83(13):4794–4798. doi: 10.1073/pnas.83.13.4794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. House C., Kemp B. E. Protein kinase C contains a pseudosubstrate prototope in its regulatory domain. Science. 1987 Dec 18;238(4834):1726–1728. doi: 10.1126/science.3686012. [DOI] [PubMed] [Google Scholar]
  34. Hynes R. O. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992 Apr 3;69(1):11–25. doi: 10.1016/0092-8674(92)90115-s. [DOI] [PubMed] [Google Scholar]
  35. Ingber D. Integrins as mechanochemical transducers. Curr Opin Cell Biol. 1991 Oct;3(5):841–848. doi: 10.1016/0955-0674(91)90058-7. [DOI] [PubMed] [Google Scholar]
  36. Izumo S., Nadal-Ginard B., Mahdavi V. Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload. Proc Natl Acad Sci U S A. 1988 Jan;85(2):339–343. doi: 10.1073/pnas.85.2.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Kamps M. P., Sefton B. M. Identification of multiple novel polypeptide substrates of the v-src, v-yes, v-fps, v-ros, and v-erb-B oncogenic tyrosine protein kinases utilizing antisera against phosphotyrosine. Oncogene. 1988 Apr;2(4):305–315. [PubMed] [Google Scholar]
  38. Kim D., Lewis D. L., Graziadei L., Neer E. J., Bar-Sagi D., Clapham D. E. G-protein beta gamma-subunits activate the cardiac muscarinic K+-channel via phospholipase A2. Nature. 1989 Feb 9;337(6207):557–560. doi: 10.1038/337557a0. [DOI] [PubMed] [Google Scholar]
  39. Kinnunen P., Vuolteenaho O., Uusimaa P., Ruskoaho H. Passive mechanical stretch releases atrial natriuretic peptide from rat ventricular myocardium. Circ Res. 1992 Jun;70(6):1244–1253. doi: 10.1161/01.res.70.6.1244. [DOI] [PubMed] [Google Scholar]
  40. Komuro I., Kaida T., Shibazaki Y., Kurabayashi M., Katoh Y., Hoh E., Takaku F., Yazaki Y. Stretching cardiac myocytes stimulates protooncogene expression. J Biol Chem. 1990 Mar 5;265(7):3595–3598. [PubMed] [Google Scholar]
  41. Komuro I., Katoh Y., Kaida T., Shibazaki Y., Kurabayashi M., Hoh E., Takaku F., Yazaki Y. Mechanical loading stimulates cell hypertrophy and specific gene expression in cultured rat cardiac myocytes. Possible role of protein kinase C activation. J Biol Chem. 1991 Jan 15;266(2):1265–1268. [PubMed] [Google Scholar]
  42. Komuro I., Kurabayashi M., Takaku F., Yazaki Y. Expression of cellular oncogenes in the myocardium during the developmental stage and pressure-overloaded hypertrophy of the rat heart. Circ Res. 1988 Jun;62(6):1075–1079. doi: 10.1161/01.res.62.6.1075. [DOI] [PubMed] [Google Scholar]
  43. Kulik T. J., Bialecki R. A., Colucci W. S., Rothman A., Glennon E. T., Underwood R. H. Stretch increases inositol trisphosphate and inositol tetrakisphosphate in cultured pulmonary vascular smooth muscle cells. Biochem Biophys Res Commun. 1991 Oct 31;180(2):982–987. doi: 10.1016/s0006-291x(05)81162-3. [DOI] [PubMed] [Google Scholar]
  44. Kurachi Y., Ito H., Sugimoto T., Shimizu T., Miki I., Ui M. Arachidonic acid metabolites as intracellular modulators of the G protein-gated cardiac K+ channel. Nature. 1989 Feb 9;337(6207):555–557. doi: 10.1038/337555a0. [DOI] [PubMed] [Google Scholar]
  45. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  46. Lang R. E., Thölken H., Ganten D., Luft F. C., Ruskoaho H., Unger T. Atrial natriuretic factor--a circulating hormone stimulated by volume loading. Nature. 1985 Mar 21;314(6008):264–266. doi: 10.1038/314264a0. [DOI] [PubMed] [Google Scholar]
  47. Magolda R. L., Galbraith W. Design and synthesis of conformationally restricted phospholipids as phospholipase A2 inhibitors. J Cell Biochem. 1989 Jul;40(3):371–386. doi: 10.1002/jcb.240400313. [DOI] [PubMed] [Google Scholar]
  48. Mann D. L., Kent R. L., Cooper G., 4th Load regulation of the properties of adult feline cardiocytes: growth induction by cellular deformation. Circ Res. 1989 Jun;64(6):1079–1090. doi: 10.1161/01.res.64.6.1079. [DOI] [PubMed] [Google Scholar]
  49. Medema R. H., Burgering B. M., Bos J. L. Insulin-induced p21ras activation does not require protein kinase C, but a protein sensitive to phenylarsine oxide. J Biol Chem. 1991 Nov 5;266(31):21186–21189. [PubMed] [Google Scholar]
  50. Meissner G. Ryanodine activation and inhibition of the Ca2+ release channel of sarcoplasmic reticulum. J Biol Chem. 1986 May 15;261(14):6300–6306. [PubMed] [Google Scholar]
  51. Moolenaar W. H., Kruijer W., Tilly B. C., Verlaan I., Bierman A. J., de Laat S. W. Growth factor-like action of phosphatidic acid. Nature. 1986 Sep 11;323(6084):171–173. doi: 10.1038/323171a0. [DOI] [PubMed] [Google Scholar]
  52. Morgan H. E., Baker K. M. Cardiac hypertrophy. Mechanical, neural, and endocrine dependence. Circulation. 1991 Jan;83(1):13–25. doi: 10.1161/01.cir.83.1.13. [DOI] [PubMed] [Google Scholar]
  53. Morgan J. I., Curran T. Role of ion flux in the control of c-fos expression. Nature. 1986 Aug 7;322(6079):552–555. doi: 10.1038/322552a0. [DOI] [PubMed] [Google Scholar]
  54. Mustelin T., Coggeshall K. M., Isakov N., Altman A. T cell antigen receptor-mediated activation of phospholipase C requires tyrosine phosphorylation. Science. 1990 Mar 30;247(4950):1584–1587. doi: 10.1126/science.2138816. [DOI] [PubMed] [Google Scholar]
  55. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science. 1992 Oct 23;258(5082):607–614. doi: 10.1126/science.1411571. [DOI] [PubMed] [Google Scholar]
  56. Nishizuka Y. The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature. 1988 Aug 25;334(6184):661–665. doi: 10.1038/334661a0. [DOI] [PubMed] [Google Scholar]
  57. Parker T. G., Schneider M. D. Growth factors, proto-oncogenes, and plasticity of the cardiac phenotype. Annu Rev Physiol. 1991;53:179–200. doi: 10.1146/annurev.ph.53.030191.001143. [DOI] [PubMed] [Google Scholar]
  58. Pelech S. L., Krebs E. G. Mitogen-activated S6 kinase is stimulated via protein kinase C-dependent and independent pathways in Swiss 3T3 cells. J Biol Chem. 1987 Aug 25;262(24):11598–11606. [PubMed] [Google Scholar]
  59. Piomelli D., Greengard P. Lipoxygenase metabolites of arachidonic acid in neuronal transmembrane signalling. Trends Pharmacol Sci. 1990 Sep;11(9):367–373. doi: 10.1016/0165-6147(90)90182-8. [DOI] [PubMed] [Google Scholar]
  60. Preiss J. E., Loomis C. R., Bell R. M., Niedel J. E. Quantitative measurement of sn-1,2-diacylglycerols. Methods Enzymol. 1987;141:294–300. doi: 10.1016/0076-6879(87)41077-x. [DOI] [PubMed] [Google Scholar]
  61. Pulverer B. J., Kyriakis J. M., Avruch J., Nikolakaki E., Woodgett J. R. Phosphorylation of c-jun mediated by MAP kinases. Nature. 1991 Oct 17;353(6345):670–674. doi: 10.1038/353670a0. [DOI] [PubMed] [Google Scholar]
  62. Riabowol K. T., Vosatka R. J., Ziff E. B., Lamb N. J., Feramisco J. R. Microinjection of fos-specific antibodies blocks DNA synthesis in fibroblast cells. Mol Cell Biol. 1988 Apr;8(4):1670–1676. doi: 10.1128/mcb.8.4.1670. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Rivera V. M., Greenberg M. E. Growth factor-induced gene expression: the ups and downs of c-fos regulation. New Biol. 1990 Sep;2(9):751–758. [PubMed] [Google Scholar]
  64. Rozengurt E. Neuropeptides as cellular growth factors: role of multiple signalling pathways. Eur J Clin Invest. 1991 Apr;21(2):123–134. doi: 10.1111/j.1365-2362.1991.tb01801.x. [DOI] [PubMed] [Google Scholar]
  65. Sadoshima J., Jahn L., Takahashi T., Kulik T. J., Izumo S. Molecular characterization of the stretch-induced adaptation of cultured cardiac cells. An in vitro model of load-induced cardiac hypertrophy. J Biol Chem. 1992 May 25;267(15):10551–10560. [PubMed] [Google Scholar]
  66. Sadoshima J., Takahashi T., Jahn L., Izumo S. Roles of mechano-sensitive ion channels, cytoskeleton, and contractile activity in stretch-induced immediate-early gene expression and hypertrophy of cardiac myocytes. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9905–9909. doi: 10.1073/pnas.89.20.9905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Satoh T., Endo M., Nakafuku M., Nakamura S., Kaziro Y. Platelet-derived growth factor stimulates formation of active p21ras.GTP complex in Swiss mouse 3T3 cells. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5993–5997. doi: 10.1073/pnas.87.15.5993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Schalasta G., Doppler C. Inhibition of c-fos transcription and phosphorylation of the serum response factor by an inhibitor of phospholipase C-type reactions. Mol Cell Biol. 1990 Oct;10(10):5558–5561. doi: 10.1128/mcb.10.10.5558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Schwartz M. A., Lechene C., Ingber D. E. Insoluble fibronectin activates the Na/H antiporter by clustering and immobilizing integrin alpha 5 beta 1, independent of cell shape. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7849–7853. doi: 10.1073/pnas.88.17.7849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Schweitzer P., Madamba S., Siggins G. R. Arachidonic acid metabolites as mediators of somatostatin-induced increase of neuronal M-current. Nature. 1990 Aug 2;346(6283):464–467. doi: 10.1038/346464a0. [DOI] [PubMed] [Google Scholar]
  71. Sei C. A., Irons C. E., Sprenkle A. B., McDonough P. M., Brown J. H., Glembotski C. C. The alpha-adrenergic stimulation of atrial natriuretic factor expression in cardiac myocytes requires calcium influx, protein kinase C, and calmodulin-regulated pathways. J Biol Chem. 1991 Aug 25;266(24):15910–15916. [PubMed] [Google Scholar]
  72. Sellmayer A., Uedelhoven W. M., Weber P. C., Bonventre J. V. Endogenous non-cyclooxygenase metabolites of arachidonic acid modulate growth and mRNA levels of immediate-early response genes in rat mesangial cells. J Biol Chem. 1991 Feb 25;266(6):3800–3807. [PubMed] [Google Scholar]
  73. Shattil S. J., Brugge J. S. Protein tyrosine phosphorylation and the adhesive functions of platelets. Curr Opin Cell Biol. 1991 Oct;3(5):869–879. doi: 10.1016/0955-0674(91)90062-4. [DOI] [PubMed] [Google Scholar]
  74. Sheng M., Greenberg M. E. The regulation and function of c-fos and other immediate early genes in the nervous system. Neuron. 1990 Apr;4(4):477–485. doi: 10.1016/0896-6273(90)90106-p. [DOI] [PubMed] [Google Scholar]
  75. Sturgill T. W., Ray L. B., Erikson E., Maller J. L. Insulin-stimulated MAP-2 kinase phosphorylates and activates ribosomal protein S6 kinase II. Nature. 1988 Aug 25;334(6184):715–718. doi: 10.1038/334715a0. [DOI] [PubMed] [Google Scholar]
  76. Takuwa N., Kumada M., Yamashita K., Takuwa Y. Mechanisms of bombesin-induced arachidonate mobilization in Swiss 3T3 fibroblasts. J Biol Chem. 1991 Aug 5;266(22):14237–14243. [PubMed] [Google Scholar]
  77. Thomas S. M., DeMarco M., D'Arcangelo G., Halegoua S., Brugge J. S. Ras is essential for nerve growth factor- and phorbol ester-induced tyrosine phosphorylation of MAP kinases. Cell. 1992 Mar 20;68(6):1031–1040. doi: 10.1016/0092-8674(92)90075-n. [DOI] [PubMed] [Google Scholar]
  78. Treisman R. The SRE: a growth factor responsive transcriptional regulator. Semin Cancer Biol. 1990 Feb;1(1):47–58. [PubMed] [Google Scholar]
  79. Tsai M. H., Yu C. L., Wei F. S., Stacey D. W. The effect of GTPase activating protein upon ras is inhibited by mitogenically responsive lipids. Science. 1989 Jan 27;243(4890):522–526. doi: 10.1126/science.2536192. [DOI] [PubMed] [Google Scholar]
  80. Tsien R. Y. New calcium indicators and buffers with high selectivity against magnesium and protons: design, synthesis, and properties of prototype structures. Biochemistry. 1980 May 27;19(11):2396–2404. doi: 10.1021/bi00552a018. [DOI] [PubMed] [Google Scholar]
  81. Ullrich A., Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990 Apr 20;61(2):203–212. doi: 10.1016/0092-8674(90)90801-k. [DOI] [PubMed] [Google Scholar]
  82. Vandenburgh H. H., Hatfaludy S., Sohar I., Shansky J. Stretch-induced prostaglandins and protein turnover in cultured skeletal muscle. Am J Physiol. 1990 Aug;259(2 Pt 1):C232–C240. doi: 10.1152/ajpcell.1990.259.2.C232. [DOI] [PubMed] [Google Scholar]
  83. Vandenburgh H. H. Mechanical forces and their second messengers in stimulating cell growth in vitro. Am J Physiol. 1992 Mar;262(3 Pt 2):R350–R355. doi: 10.1152/ajpregu.1992.262.3.R350. [DOI] [PubMed] [Google Scholar]
  84. Vandenburgh H., Kaufman S. In vitro model for stretch-induced hypertrophy of skeletal muscle. Science. 1979 Jan 19;203(4377):265–268. doi: 10.1126/science.569901. [DOI] [PubMed] [Google Scholar]
  85. Wang L. Y., Salter M. W., MacDonald J. F. Regulation of kainate receptors by cAMP-dependent protein kinase and phosphatases. Science. 1991 Sep 6;253(5024):1132–1135. doi: 10.1126/science.1653455. [DOI] [PubMed] [Google Scholar]
  86. Watson P. A. Accumulation of cAMP and calcium in S49 mouse lymphoma cells following hyposmotic swelling. J Biol Chem. 1989 Sep 5;264(25):14735–14740. [PubMed] [Google Scholar]
  87. Watson P. A. Function follows form: generation of intracellular signals by cell deformation. FASEB J. 1991 Apr;5(7):2013–2019. doi: 10.1096/fasebj.5.7.1707019. [DOI] [PubMed] [Google Scholar]
  88. Williams L. T. Signal transduction by the platelet-derived growth factor receptor. Science. 1989 Mar 24;243(4898):1564–1570. doi: 10.1126/science.2538922. [DOI] [PubMed] [Google Scholar]
  89. Wirtz H. R., Dobbs L. G. Calcium mobilization and exocytosis after one mechanical stretch of lung epithelial cells. Science. 1990 Nov 30;250(4985):1266–1269. doi: 10.1126/science.2173861. [DOI] [PubMed] [Google Scholar]
  90. Wood K. W., Sarnecki C., Roberts T. M., Blenis J. ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK. Cell. 1992 Mar 20;68(6):1041–1050. doi: 10.1016/0092-8674(92)90076-o. [DOI] [PubMed] [Google Scholar]
  91. Wrighton S. A., Pai J. K., Mueller G. C. Demonstration of two unique metabolites of arachidonic acid from phorbol ester-stimulated bovine lymphocytes. Carcinogenesis. 1983 Oct;4(10):1247–1251. doi: 10.1093/carcin/4.10.1247. [DOI] [PubMed] [Google Scholar]
  92. Xenophontos X. P., Watson P. A., Chua B. H., Haneda T., Morgan H. E. Increased cyclic AMP content accelerates protein synthesis in rat heart. Circ Res. 1989 Sep;65(3):647–656. doi: 10.1161/01.res.65.3.647. [DOI] [PubMed] [Google Scholar]
  93. von Harsdorf R., Lang R. E., Fullerton M., Woodcock E. A. Myocardial stretch stimulates phosphatidylinositol turnover. Circ Res. 1989 Aug;65(2):494–501. doi: 10.1161/01.res.65.2.494. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES