Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Jul 3;92(14):6582–6586. doi: 10.1073/pnas.92.14.6582

A kinase associated with chromatin that can be activated by ligand-p185c-Neu or epidermal growth factor-receptor interactions.

A Samanta 1, M I Greene 1
PMCID: PMC41562  PMID: 7604037

Abstract

Some growth factors transduce positive growth signals, while others can act as growth inhibitors. Nuclear signaling events of previously quiescent cells stimulated with various growth factors have been studied by isolating the complexed chromatin-associated proteins and chromatin-associated proteins. Signals from the plasma membrane are integrated within the cells and quickly transduced to the nucleus. It is clear that several growth factors, such as epidermal growth factor, transforming growth factor alpha (but not transforming growth factor beta), and platelet-derived growth factor, utilize similar intracellular signaling biochemistries to modulate nucleosomal characteristics. The very rapid and consistent phosphorylation of nuclear p33, p54, and low molecular mass proteins in the range of 15-18 kDa after growth factor stimulation implies that there is a coordination and integration of the cellular signaling processes. Additionally, phosphorylation of p33 and some low molecular mass histones has been found to occur within 5 min of growth factor treatment and to reach a maximum by 30 min. In this study, we report that Neu receptor activating factor also utilizes the same signaling mechanism and causes p33 to become phosphorylated. In addition, both the tumor promoter okadaic acid (which inhibits protein phosphatases 1 and 2A) and phorbol ester (phorbol 12-tetradecanoate 13-acetate) stimulate phosphorylation of p33, p54, and low molecular mass histones. However, transforming growth factor beta, which is a growth inhibitor for fibroblasts, fails to increase p33 phosphorylation. In general, p33 phosphorylation patterns correspond to positive and negative mitogenic signal transduction. p33 isolated from the complexed chromatin-associated protein fraction appears to be a kinase, or tightly associated with a kinase, and shares antigenicity with the cell division cycle-dependent Cdk2 kinase as determined by antibody-dependent analysis. The rapid phosphorylation of nucleosomal proteins may influence sets of early genes needed for the induction and progression of the cell cycle.

Full text

PDF
6582

Images in this article

6583Fig. 1
on p.6583
6584Fig. 2
on p.6584
6584Fig. 3
on p.6584
6585Fig. 4
on p.6585
6585Fig. 5
on p.6585

Selected References

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

  1. Arion D., Meijer L., Brizuela L., Beach D. cdc2 is a component of the M phase-specific histone H1 kinase: evidence for identity with MPF. Cell. 1988 Oct 21;55(2):371–378. doi: 10.1016/0092-8674(88)90060-8. [DOI] [PubMed] [Google Scholar]
  2. Berridge M. J., Irvine R. F. Inositol phosphates and cell signalling. Nature. 1989 Sep 21;341(6239):197–205. doi: 10.1038/341197a0. [DOI] [PubMed] [Google Scholar]
  3. Blenis J. Signal transduction via the MAP kinases: proceed at your own RSK. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5889–5892. doi: 10.1073/pnas.90.13.5889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Blow J. J., Nurse P. A cdc2-like protein is involved in the initiation of DNA replication in Xenopus egg extracts. Cell. 1990 Sep 7;62(5):855–862. doi: 10.1016/0092-8674(90)90261-c. [DOI] [PubMed] [Google Scholar]
  5. Carpenter G., Cohen S. Epidermal growth factor. J Biol Chem. 1990 May 15;265(14):7709–7712. [PubMed] [Google Scholar]
  6. Cheifetz S., Bellón T., Calés C., Vera S., Bernabeu C., Massagué J., Letarte M. Endoglin is a component of the transforming growth factor-beta receptor system in human endothelial cells. J Biol Chem. 1992 Sep 25;267(27):19027–19030. [PubMed] [Google Scholar]
  7. D'Urso G., Marraccino R. L., Marshak D. R., Roberts J. M. Cell cycle control of DNA replication by a homologue from human cells of the p34cdc2 protein kinase. Science. 1990 Nov 9;250(4982):786–791. doi: 10.1126/science.2173140. [DOI] [PubMed] [Google Scholar]
  8. Dahms N. M., Lobel P., Kornfeld S. Mannose 6-phosphate receptors and lysosomal enzyme targeting. J Biol Chem. 1989 Jul 25;264(21):12115–12118. [PubMed] [Google Scholar]
  9. Davis R. J. The mitogen-activated protein kinase signal transduction pathway. J Biol Chem. 1993 Jul 15;268(20):14553–14556. [PubMed] [Google Scholar]
  10. Devoto S. H., Mudryj M., Pines J., Hunter T., Nevins J. R. A cyclin A-protein kinase complex possesses sequence-specific DNA binding activity: p33cdk2 is a component of the E2F-cyclin A complex. Cell. 1992 Jan 10;68(1):167–176. doi: 10.1016/0092-8674(92)90215-x. [DOI] [PubMed] [Google Scholar]
  11. Dobashi K., Davis J. G., Mikami Y., Freeman J. K., Hamuro J., Greene M. I. Characterization of a neu/c-erbB-2 protein-specific activating factor. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8582–8586. doi: 10.1073/pnas.88.19.8582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dulić V., Lees E., Reed S. I. Association of human cyclin E with a periodic G1-S phase protein kinase. Science. 1992 Sep 25;257(5078):1958–1961. doi: 10.1126/science.1329201. [DOI] [PubMed] [Google Scholar]
  13. Dunphy W. G., Brizuela L., Beach D., Newport J. The Xenopus cdc2 protein is a component of MPF, a cytoplasmic regulator of mitosis. Cell. 1988 Jul 29;54(3):423–431. doi: 10.1016/0092-8674(88)90205-x. [DOI] [PubMed] [Google Scholar]
  14. Enoch T., Nurse P. Coupling M phase and S phase: controls maintaining the dependence of mitosis on chromosome replication. Cell. 1991 Jun 14;65(6):921–923. doi: 10.1016/0092-8674(91)90542-7. [DOI] [PubMed] [Google Scholar]
  15. Fang F., Newport J. W. Evidence that the G1-S and G2-M transitions are controlled by different cdc2 proteins in higher eukaryotes. Cell. 1991 Aug 23;66(4):731–742. doi: 10.1016/0092-8674(91)90117-h. [DOI] [PubMed] [Google Scholar]
  16. Fang F., Newport J. W. Evidence that the G1-S and G2-M transitions are controlled by different cdc2 proteins in higher eukaryotes. Cell. 1991 Aug 23;66(4):731–742. doi: 10.1016/0092-8674(91)90117-h. [DOI] [PubMed] [Google Scholar]
  17. Greenberg M. E., Ziff E. B. Stimulation of 3T3 cells induces transcription of the c-fos proto-oncogene. Nature. 1984 Oct 4;311(5985):433–438. doi: 10.1038/311433a0. [DOI] [PubMed] [Google Scholar]
  18. Hunter T., Pines J. Cyclins and cancer. Cell. 1991 Sep 20;66(6):1071–1074. doi: 10.1016/0092-8674(91)90028-w. [DOI] [PubMed] [Google Scholar]
  19. Johnson D., Lanahan A., Buck C. R., Sehgal A., Morgan C., Mercer E., Bothwell M., Chao M. Expression and structure of the human NGF receptor. Cell. 1986 Nov 21;47(4):545–554. doi: 10.1016/0092-8674(86)90619-7. [DOI] [PubMed] [Google Scholar]
  20. Kiefer M. C., Stephans J. C., Crawford K., Okino K., Barr P. J. Ligand-affinity cloning and structure of a cell surface heparan sulfate proteoglycan that binds basic fibroblast growth factor. Proc Natl Acad Sci U S A. 1990 Sep;87(18):6985–6989. doi: 10.1073/pnas.87.18.6985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Koff A., Ohtsuki M., Polyak K., Roberts J. M., Massagué J. Negative regulation of G1 in mammalian cells: inhibition of cyclin E-dependent kinase by TGF-beta. Science. 1993 Apr 23;260(5107):536–539. doi: 10.1126/science.8475385. [DOI] [PubMed] [Google Scholar]
  22. Kokai Y., Cohen J. A., Drebin J. A., Greene M. I. Stage- and tissue-specific expression of the neu oncogene in rat development. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8498–8501. doi: 10.1073/pnas.84.23.8498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Krebs E. G., Eisenman R. N., Kuenzel E. A., Litchfield D. W., Lozeman F. J., Lüscher B., Sommercorn J. Casein kinase II as a potentially important enzyme concerned with signal transduction. Cold Spring Harb Symp Quant Biol. 1988;53(Pt 1):77–84. doi: 10.1101/sqb.1988.053.01.012. [DOI] [PubMed] [Google Scholar]
  24. Lamph W. W., Wamsley P., Sassone-Corsi P., Verma I. M. Induction of proto-oncogene JUN/AP-1 by serum and TPA. Nature. 1988 Aug 18;334(6183):629–631. doi: 10.1038/334629a0. [DOI] [PubMed] [Google Scholar]
  25. López-Casillas F., Cheifetz S., Doody J., Andres J. L., Lane W. S., Massagué J. Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-beta receptor system. Cell. 1991 Nov 15;67(4):785–795. doi: 10.1016/0092-8674(91)90073-8. [DOI] [PubMed] [Google Scholar]
  26. López-Casillas F., Wrana J. L., Massagué J. Betaglycan presents ligand to the TGF beta signaling receptor. Cell. 1993 Jul 2;73(7):1435–1444. doi: 10.1016/0092-8674(93)90368-z. [DOI] [PubMed] [Google Scholar]
  27. MacDonald R. G., Pfeffer S. R., Coussens L., Tepper M. A., Brocklebank C. M., Mole J. E., Anderson J. K., Chen E., Czech M. P., Ullrich A. A single receptor binds both insulin-like growth factor II and mannose-6-phosphate. Science. 1988 Mar 4;239(4844):1134–1137. doi: 10.1126/science.2964083. [DOI] [PubMed] [Google Scholar]
  28. Mahadevan L. C., Edwards D. R. Signalling and superinduction. Nature. 1991 Feb 28;349(6312):747–748. doi: 10.1038/349747c0. [DOI] [PubMed] [Google Scholar]
  29. Mahadevan L. C., Willis A. C., Barratt M. J. Rapid histone H3 phosphorylation in response to growth factors, phorbol esters, okadaic acid, and protein synthesis inhibitors. Cell. 1991 May 31;65(5):775–783. doi: 10.1016/0092-8674(91)90385-c. [DOI] [PubMed] [Google Scholar]
  30. Majerus P. W., Ross T. S., Cunningham T. W., Caldwell K. K., Jefferson A. B., Bansal V. S. Recent insights in phosphatidylinositol signaling. Cell. 1990 Nov 2;63(3):459–465. doi: 10.1016/0092-8674(90)90442-h. [DOI] [PubMed] [Google Scholar]
  31. McCormick F. Signal transduction. How receptors turn Ras on. Nature. 1993 May 6;363(6424):15–16. doi: 10.1038/363015a0. [DOI] [PubMed] [Google Scholar]
  32. Morgan D. O., Edman J. C., Standring D. N., Fried V. A., Smith M. C., Roth R. A., Rutter W. J. Insulin-like growth factor II receptor as a multifunctional binding protein. Nature. 1987 Sep 24;329(6137):301–307. doi: 10.1038/329301a0. [DOI] [PubMed] [Google Scholar]
  33. Murray A. W., Kirschner M. W. Cyclin synthesis drives the early embryonic cell cycle. Nature. 1989 May 25;339(6222):275–280. doi: 10.1038/339275a0. [DOI] [PubMed] [Google Scholar]
  34. 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]
  35. Nurse P. Ordering S phase and M phase in the cell cycle. Cell. 1994 Nov 18;79(4):547–550. doi: 10.1016/0092-8674(94)90539-8. [DOI] [PubMed] [Google Scholar]
  36. Nurse P. Universal control mechanism regulating onset of M-phase. Nature. 1990 Apr 5;344(6266):503–508. doi: 10.1038/344503a0. [DOI] [PubMed] [Google Scholar]
  37. Ohtsubo M., Roberts J. M. Cyclin-dependent regulation of G1 in mammalian fibroblasts. Science. 1993 Mar 26;259(5103):1908–1912. doi: 10.1126/science.8384376. [DOI] [PubMed] [Google Scholar]
  38. Pagano M., Draetta G., Jansen-Dürr P. Association of cdk2 kinase with the transcription factor E2F during S phase. Science. 1992 Feb 28;255(5048):1144–1147. doi: 10.1126/science.1312258. [DOI] [PubMed] [Google Scholar]
  39. Pagano M., Pepperkok R., Verde F., Ansorge W., Draetta G. Cyclin A is required at two points in the human cell cycle. EMBO J. 1992 Mar;11(3):961–971. doi: 10.1002/j.1460-2075.1992.tb05135.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Paris J., Le Guellec R., Couturier A., Le Guellec K., Omilli F., Camonis J., MacNeill S., Philippe M. Cloning by differential screening of a Xenopus cDNA coding for a protein highly homologous to cdc2. Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):1039–1043. doi: 10.1073/pnas.88.3.1039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Qian X., Dougall W. C., Hellman M. E., Greene M. I. Kinase-deficient neu proteins suppress epidermal growth factor receptor function and abolish cell transformation. Oncogene. 1994 May;9(5):1507–1514. [PubMed] [Google Scholar]
  42. Qian X., LeVea C. M., Freeman J. K., Dougall W. C., Greene M. I. Heterodimerization of epidermal growth factor receptor and wild-type or kinase-deficient Neu: a mechanism of interreceptor kinase activation and transphosphorylation. Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1500–1504. doi: 10.1073/pnas.91.4.1500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Quantin B., Breathnach R. Epidermal growth factor stimulates transcription of the c-jun proto-oncogene in rat fibroblasts. Nature. 1988 Aug 11;334(6182):538–539. doi: 10.1038/334538a0. [DOI] [PubMed] [Google Scholar]
  44. Radeke M. J., Misko T. P., Hsu C., Herzenberg L. A., Shooter E. M. Gene transfer and molecular cloning of the rat nerve growth factor receptor. Nature. 1987 Feb 12;325(6105):593–597. doi: 10.1038/325593a0. [DOI] [PubMed] [Google Scholar]
  45. Rapp U. R., Heidecker G., Huleihel M., Cleveland J. L., Choi W. C., Pawson T., Ihle J. N., Anderson W. B. raf family serine/threonine protein kinases in mitogen signal transduction. Cold Spring Harb Symp Quant Biol. 1988;53(Pt 1):173–184. doi: 10.1101/sqb.1988.053.01.023. [DOI] [PubMed] [Google Scholar]
  46. Rosenblatt J., Gu Y., Morgan D. O. Human cyclin-dependent kinase 2 is activated during the S and G2 phases of the cell cycle and associates with cyclin A. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2824–2828. doi: 10.1073/pnas.89.7.2824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Ryseck R. P., Hirai S. I., Yaniv M., Bravo R. Transcriptional activation of c-jun during the G0/G1 transition in mouse fibroblasts. Nature. 1988 Aug 11;334(6182):535–537. doi: 10.1038/334535a0. [DOI] [PubMed] [Google Scholar]
  48. Samanta A., LeVea C. M., Dougall W. C., Qian X., Greene M. I. Ligand and p185c-neu density govern receptor interactions and tyrosine kinase activation. Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1711–1715. doi: 10.1073/pnas.91.5.1711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Saunders S., Jalkanen M., O'Farrell S., Bernfield M. Molecular cloning of syndecan, an integral membrane proteoglycan. J Cell Biol. 1989 Apr;108(4):1547–1556. doi: 10.1083/jcb.108.4.1547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Schechter A. L., Stern D. F., Vaidyanathan L., Decker S. J., Drebin J. A., Greene M. I., Weinberg R. A. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature. 1984 Dec 6;312(5994):513–516. doi: 10.1038/312513a0. [DOI] [PubMed] [Google Scholar]
  51. Sorkin A., Carpenter G. Interaction of activated EGF receptors with coated pit adaptins. Science. 1993 Jul 30;261(5121):612–615. doi: 10.1126/science.8342026. [DOI] [PubMed] [Google Scholar]
  52. 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]
  53. Tsai L. H., Harlow E., Meyerson M. Isolation of the human cdk2 gene that encodes the cyclin A- and adenovirus E1A-associated p33 kinase. Nature. 1991 Sep 12;353(6340):174–177. doi: 10.1038/353174a0. [DOI] [PubMed] [Google Scholar]
  54. 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]
  55. Wada T., Qian X. L., Greene M. I. Intermolecular association of the p185neu protein and EGF receptor modulates EGF receptor function. Cell. 1990 Jun 29;61(7):1339–1347. doi: 10.1016/0092-8674(90)90697-d. [DOI] [PubMed] [Google Scholar]
  56. Wang X. F., Lin H. Y., Ng-Eaton E., Downward J., Lodish H. F., Weinberg R. A. Expression cloning and characterization of the TGF-beta type III receptor. Cell. 1991 Nov 15;67(4):797–805. doi: 10.1016/0092-8674(91)90074-9. [DOI] [PubMed] [Google Scholar]
  57. Weiner D. B., Liu J., Cohen J. A., Williams W. V., Greene M. I. A point mutation in the neu oncogene mimics ligand induction of receptor aggregation. Nature. 1989 May 18;339(6221):230–231. doi: 10.1038/339230a0. [DOI] [PubMed] [Google Scholar]
  58. Zentella A., Massagué J. Transforming growth factor beta induces myoblast differentiation in the presence of mitogens. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):5176–5180. doi: 10.1073/pnas.89.11.5176. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES