Cyclic AMP-mediated inhibition of cell growth requires the small G protein Rap1

Molecular and Cellular Biology

Volumn 21, Issue 11, 2001, Pages 3671-3683

  Schmitt, John M ^a   Stork, Philip J S ^a  

^a OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLIC AMP; GUANINE NUCLEOTIDE BINDING PROTEIN; MITOGEN ACTIVATED PROTEIN KINASE; RAF PROTEIN; RAP PROTEIN; RAS PROTEIN;

ANIMAL CELL; ARTICLE; CELL CYCLE; CELL GROWTH; CELL PROLIFERATION; CELL TRANSFORMATION; CONTROLLED STUDY; EMBRYO; ENZYME ACTIVATION; ENZYME INHIBITION; GROWTH INHIBITION; HUMAN; HUMAN CELL; MITOGENESIS; MOUSE; NONHUMAN; PRIORITY JOURNAL;

3T3 CELLS; ANIMALS; CELL DIVISION; CELL LINE, TRANSFORMED; CYCLIC AMP; HUMANS; MICE; MITOGEN-ACTIVATED PROTEIN KINASE 1; MITOGEN-ACTIVATED PROTEIN KINASE 3; MITOGEN-ACTIVATED PROTEIN KINASES; PROTO-ONCOGENE PROTEINS C-RAF; RAP1 GTP-BINDING PROTEINS; RAS PROTEINS;

ANIMALIA;

EID: 0034996666     PISSN: 02707306     EISSN: None     Source Type: Journal    
DOI: 10.1128/MCB.21.11.3671-3683.2001     Document Type: Article

References (119)

1. Ahn, N. G. 1993. The MAP kinase cascade. Discovery of a new signal transduction pathway. Mol. Cell. Biochem. 127-128:201-209.
2. Alest, L. V., M. Barr, S. Marcus, A. Polverino, and M. Wigler. 1993. Complex formation between RAS and RAF and other protein kinases. Proc. Natl. Acad. Sci. USA 90:6213-6217.
3. Altschuler, D., and E. G. Lapetina. 1993. Mutational analysis of the cAMP-dependent protein kinase-mediated phosphorylation site of Rap1b. J. Biol. Chem. 268:7527-7531.
4. Altschuler, D. L., S. N. Peterson, M. C. Ostrowski, and E. G. Lapetina. 1995. Cyclic AMP-dependent activation of Rap1b. J. Biol. Chem. 270: 10373-10376.
5. Altschuler, D. L., and F. Ribeiro-Neto. 1998. Mitogenic and oncogenic properties of the small G protein Rap1b. Proc. Natl. Acad. Sci. USA 95:7475-7479.
6. Anneren, C., K. A. Reedquist, J. L. Bos, and M. Welsh. 2000. GTK, a Src-related tyrosine kinase, induces nerve growth factor-independent neurite outgrowth in PC12 cells through activation of the Rap1 pathway. Relationship to Shb tyrosine phosphorylation and elevated levels of focal adhesion kinase. J. Biol. Chem. 275:29153-29161.
7. Avruch, J., X.-F. Zhang, and J. M. Kyriakis. 1994. Raf meets Ras: completing the framework of a signal transduction pathway. Trends Biochem. Sci. 19:279-283.
8. Blenis, J. 1993. Signal transduction via the MAP kinases: proceed at your own RSK. Proc. Natl. Acad. Sci. USA 90:5889-5892.
9. Bos, J. L. 1998. All in the family? New insights and questions regarding interconnectivity of Ras, Rap1 and Ral. EMBO J. 17:6776-6782.
10. Burgering, B. M., G. J. Pronk, P. C. van Weeren, P. Chardin, and J. L. Bos. 1993. cAMP antagonizes p21ras-directed activation of extracellular signal-regulated kinase 2 and phosphorylation of mSos nucleotide exchange factor. EMBO J. 12:4211-4220.
11. Busca, R., P. Abbe, F. Mantoux, E. Aberdam, C. Peyssonnaux, A. Eychene, J. P. Ortonne, and R. Ballotti. 2000. Ras mediates the cAMP-dependent activation of extracellular signal-regulated kinases (ERKs) in melanocytes. EMBO J. 19:2900-2910.
12. Campa, M. J., K.-J. Chang, L. Molina y Vedia, B. R. Reep, and E. G. Lapetina. 1991. Inhibition of ras-induced germinal vesicle breakdown in Xenopus oocytes by rap-1B. Biochem. Biophys. Res. Commun. 174:1-5.
13. Chen, J., and R. Iyengar. 1994. Suppression of Ras-induced transformation of NIH 3T3 cells by activated Gαs. Science 263:1278-1281.
14. Chijiwa, T., A. Mishima, M. Hagiwara, M. Sano, K. Hayashi, T. Inoue, K. Naito, T. Toshioka, and H. Hidaka. 1990. Inhibition of forskolin-induced neurite outgrowth and protein phosphorylation by a newly synthesized selective inhibitor of cyclic AMP-dependent protein kinase, N-[2-(p-bromocinnamylamino) etnyl]-5-isoquinolinesulfonamide (H-89), of PC12D pheochromocytoma cells. J. Biol. Chem. 265:5267-5272.
15. Cobb, M. H., and E. J. Goldsmith. 1995. How MAP kinases are regulated. J. Biol. Chem. 270:14843-14846.
16. Cobellis, G., C. Missero, and R. Di Lauro. 1998. Concomitant activation of MEK-1 and Rac-1 increases the proliferative potential of thyroid epithelial cells, without affecting their differentiation. Oncogene 17:2047-2057.
17. Cook, S. J., and F. McCormick. 1993. Inhibition by cAMP of Ras-dependent activation of Raf. Science 262:1069-1072.
18. Cook, S. J., B. Rubinfeld, I. Albert, and F. McCormick, 1993. RapV12 antagonizes Ras-dependent activation of ERK1 and ERK2 by LPA and EGF in Rat-1 fibroblasts. EMBO J. 12:3475-3485.
19. Cowley, S., H. Paterson, P. Kemp, and C. J. Marshall. 1994. Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH3T3 cells. Cell 77:841-852.
20. Crews, C. M., and R. L. Erikson. 1993. Extracellular signals and reversible protein phosphorylation: what to Mek of it all. Cell 74:215-217.
21. Daaka, Y., L. M. Luttrell, and R. J. Lefkowitz. 1997. Switching of the coupling of the beta2-adrenergic receptor to different G proteins by protein kinase A. Nature 390:88-91.
22. Day, R. N., J. A. Walder, and R. A. Maurer. 1989. A protein kinase inhibitor gene reduces both basal and multihormone-stimulated prolactin gene transcription. J. Biol. Chem. 264:431-436.
23. de Rooij, J., F. J. Zwartkruis, M. H. Verheijen, R. H. Cool, S. M. Nijman, A. Wittinghofer, and J. L. Bos. 1998. Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 396:474-477.
24. de Ruiter, N. D., R. M. Wolthuis, H. van Dam, B. M. Burgering, and J. L. Bos. 2000. Ras-dependent regulation of c-Jun phosphorylation is mediated by the ral guanine nucleotide exchange factor-Ral pathway. Mol. Cell. Biol. 20:8480-8488.
25. Dhanasekaran, N., L. E. Heasley, and G. L. Johnson. 1995. G protein-coupled receptor systems involved in cell growth and oncogenesis. Endocrine Rev. 16:259-270.
26. Downward, J. 1998. Ras signalling and apoptosis. Curr. Opin. Genet. Dev. 8:49-54.
27. Downward, J. 1995. A target for Pl(3) kinase. Nature 376:553-554.
28. Dremier, S., F. Vandeput, F. J. Zwartkruis, J. L. Bos, J. E. Dumont, and C. Maenhaut. 2000. Activation of the small G protein Rap1 in dog thyroid cells by both cAMP-dependent and -independent pathways. Biochem. Biophys. Res. Commun. 267:7-11.
29. Dugan, L. L., J. S. Kim, Y. Zhang, R. D. Bart, Y. Sun, D. M. Holtzman, and D. H. Gutmann. 1999. Differential effects of cAMP in neurons and astrocytes. Role of B-raf. J. Biol. Chem. 274:25842-25848.
30. Feig, L. A., and G. M. Cooper. 1988. Inhibition of NIH 3T3 cell proliferation by a mutant Ras protein with preferential afFinity for GDP. Mol. Cell. Biol. 8:3235-3243.
31. 2+-mediated activation of rap1 in human platelets. EMBO J. 16:252-259.
32. Franke, B., M. van Triest, K. M. de Bruijn, G. van Willigen, H. K. Nieuwenhuis, C. Negrier, J. W. Akkerman, and J. L. Bos. 2000. Sequential regulation of the small GTPase Rap1 in human platelets. Mol. Cell. Biol. 20:779-785.
33. Franke, T. F., D. R. Kaplan, and L. C. Cantley. 1997. PI3K: downstream AKTion blocks apoptosis. Cell 88:435-437.
34. Gille, H., and J. Downward. 1999. Multiple ras effector pathways contribute to G(1) cell cycle progression. J. Biol. Chem. 274:22033-22040.
35. Gong, Q., A. M. Cheng, A. M. Akk, J. Alerola-Ila, G. Gong, T. Pawson, and A. C. Chan. 2000. Disruption of T cell signaling networks and development by Grb2 haploid insufficiency. Nat. Immunol. 2:29-36.
36. Graves, L. M., K. E. Bornfeldt, E. W. Raines, B. C. Potts, S. G. Macdonald, R. Ross, and E. G. Krebs. 1993. Protein kinase A antagonizes platelet-derived growth factor-induced signaling by mitogen-activated protein kinase in human arterial smooth muscle cells. Proc. Natl. Acad. Sci. USA 90:10300-10304.
37. Graves, L. M, H. I. Guy, P. Kozlowski, M. Huang, E. Lazarowski, R. M. Pope, M. A. Collins, E. N. Dahlstrand, H. S. Earp III, and D. R. Evans. 2000. Regulation of carbamoyl phosphate synthetase by MAP kinase. Nature 403:328-332.
38. Hafner, S., H. S. Adler, H. Mischak, P. Janosch, G. Heidecker, A. Wolfman, S. Pippig, M. Lohse, M. Ueffing, and W. Kolch. 1994. Mechanism of inhibition of Raf-1 by protein kinase A. Mol. Cell. Biol. 14:6696-6703.
39. Hata, Y., K. Kaibuchi, S. Kawamura, M. Hiroyoshi, H. Shirataki, and Y. Takai. 1991. Enhancement of the actions of smg p21 GDP/GTP exchange protein by the protein kinase A-catalyzed phosphorylation of smg p21. J. Biol. Chem. 266:6571-6577.
40. Hernandez-Munoz, I., M. Malumbres, P. Leonardi, and A. Pellicer. 2000. The Rgr oncogene (homologous to RalGDS) induces transformation and gene expression by activating Ras, Ral and Rho mediated pathways. Oncogene 19:2745-2757.
41. Herrmann, C., G. Horn, M. Spaargaren, and A. Wittinghofer. 1996. Differential interaction of the ras family GTP-hinding proteins H-Ras, Rap1A, and R-Ras with the putative effector molecules Raf kinase and Ral-guanine nucleotide exchange factor. J. Biol. Chem. 271:6794-6800.
42. Howe, A. K., and R. L. Juliano. 2000. Regulation of anchorage-dependent signal transduction by protein kinase A and p21-activaled kinase. Nat. Cell Biol. 2:593-600.
43. Hu, C. D., K. Kariya, T. Okada, X. Qi, C. Song, and T. Kataoka. 1999. Effect of phosphorylation on activities of Rap1A to interact with Raf-1 and to suppress Ras-dependent Raf-1 activation. J. Biol. Chem. 274:48-51.
44. Hu, C. D., K. Kariya, G. Kotani, M. Shirouzu, S. Yokoyama, and T. Kataoka. 1997. Coassociation of Rap1A and Ha-Ras with Raf-1 N-terminal region interferes with ras-dependent activation of Raf-1. J. Biol. Chem. 272:11702-11705.
45. Indolfi, C., E. V. Avvedimento, E. Di Lorenzo, G. Esposito, A. Rapacciuolo, P. Giuliano, D. Grieco, L. Cavuto, A. M. Stingone, I. Ciullo, G. Condorelli, and M. Chiariello. 1997. Activation of cAMP-PKA signaling in vivo inhibits smooth muscle cell proliferation induced by vascular injury. Nat. Med. 3:775-779.
46. Innocente, S. A., J. L. Abrahamson, J. P. Cogswell, and J. M. Lee. 1999. p53 regulates a G2 checkpoint through cyclin B1. Proc. Natl. Acad. Sci. USA 96:2147-2152.
47. Joyce, D., B. Bouzahzah, M. Fu, C. Albanese, M. D'Amico, J. Steer, J. U. Klein, R. J. Lee, J. E. Segall, J. K. Westwick, C. J. Der, and R. G. Pestell. 1999. Integration of Rac-dependent regulation of cyclin D1 transcription through a nuclear factor-kappaB-dependent pathway. J. Biol. Chem. 274: 25245-25249.
48. Kawada, M., S. Yamagoe, Y. Murakami, K. Suzuki, S. Mizuno, and Y. Uehara. 1997. Induction of p27Kip1 degradation and anchorage independence by Ras through the MAP kinase signaling pathway. Oncogene 15: 629-637.
49. Kawasaki, H., G. M. Springett, N. Mochizuki, S. Toki, M. Nakaya, M. Matsuda, D. E. Housman, and A. M. Graybiel. 1998. A family of cAMP-binding proteins that directly activate Rap1. Science 282:2275-2279.
50. Kerkhoff, E., and U. R. Rapp. 1997. Induction of cell proliferation in quiescent NIH 3T3 cells by oncogenic c-Raf-1. Mol. Cell. Biol. 17:2576-2586.
51. Khosravi-Far, R., M. A. White, J. K. Westwick, P. A. Solski, M. Chrzanowska-Wodnicka, L. Van Aelst, M. H. Wigler, and C. J. Der. 1996. Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation. Mol. Cell. Biol. 16:3923-3933.
52. Kikuchi, A., and L. T. Williams. 1996. Regulation of interaction of ras p21 with Ra1GDS and Raf-1 by cyclic AMP-dependent protein kinase. J. Biol. Chem. 271:588-594.
53. Kim, H. A., J. E. DeClue, and N. Ratner. 1997. cAMP-dependent protein kinase A is required for Schwann cell growth: interactions between the cAMP and neuregulin/tyrosine kinase pathways. J. Neurosci. Res. 49:236-247.
54. Kitayama, H., Y. Sugimoto, T. Matsuzaki, Y. Ikawa, and M. Noda. 1989. A ras-related gene with transformation suppressor activity. Cell 56:77-84.
55. ras. Proc. Natl. Acad. Sci. USA 91:12706-12710.
56. Koch, W. J., J. Inglese, W. C. Stone, and R. J. Lefkowitz. 1993. The binding site for the beta gamma subunits of heterotrimeric G proteins on the beta-adrenergic receptor kinase. J. Biol. Chem. 268:8256-8260.
57. Kolch, W., G. Heidecker, P. Lloyd, and U. R. Rapp. 1991. Raf-1 protein kinase is required for growth of induced NIH/3T3 cells. Nature 349:426-428.
58. Lavoie, J. N., G. L'Allemain, A. Brunet, R. Muller, and J. Pouyssegur. 1996. Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively hy the p38/HOGMAPK pathway. J. Biol. Chem. 271:20608-20616.
59. Leevers, S. J., and C. J. Marshall. 1992. MAP kinase regulation - the oncogene connection. Trends Cell Biol. 2:283-286.
60. Lewis, T. S., P. S. Shapiro, and N. G. Ahn. 1998. Signal transduction through MAP kinase cascades. Adv. Cancer Res. 74:49-139.
61. Lin, Y., C. Mettling, and C. Chou. 2000. Rap1-suppressed tumorigenesis is concomitant with the interference in ras effector signaling. FEBS Lett. 467:184-188.
62. Lopez-Llasaca, M., P. Crespo, P. G. Pellicci, J. S. Gutkind, and R. Wetzker. 1997. Linkage of G protein-coupled receptors to the MAPK signaling pathway through P1 3-kinase γ. Science 275:394-397.
63. MacNicol, M. C., and A. M. MacNicol. 1999. Nerve growth factor-stimulated B-Raf catalytic activity is refractory to inhibition by cAMP-dependent protein kinase. J. Biol. Chem. 274:13193-13197.
64. Mansour, S. J., W. T. Matten, A. S. Hermann, J. M. Candia, S. Rong, K. Fukasawa, G. F. V. Woude, and N. G. Ahn. 1994. Transformation of mammalian cells by constitutively active MAP kinase kinase. Science 265:966-970.
65. McKenzie, F. R., and J. Pouyssegur. 1996. cAMP-mediated growth inhibition in fibroblasts is not mediated via mitogen-activated protein (MAP) kinase (ERK) inhibition. cAMP-dependent protein kinase induces a temporal shift in growth factor-stimulated MAP kinases. J. Biol. Chem. 271: 13476-13483.
66. Miller, M. J., S. Prigent, E. Kupperman, L. Rioux, S. H. Park, J. R. Feramisco, M. A. White, J. L. Rutkowski, and J. L. Meinkoth. 1997. RalGDS functions in Ras-and cAMP-mediated growth stimulation. J. Biol. Chem. 272:5600-5605.
67. Mischak, H., T. Seitz, P. Janosch, M. Eulitz, H. Steen, M. Schellerer, A. Philipp, and W. Kolch. 1996. Negative regulation of Raf-1 by phosphorylation of serine 621. Mol. Cell. Biol. 16:5409-5418.
68. Moodie, S. A., B. M. Willumsen, M. J. Weber, and A. Wolfman. 1993. Complexes of ras.GTP with raf-1 and mitogen-activated protein kinase kinase. Science 260:1658-1661.
69. Moore, K. A., R. Sethi, A. M. Doanes, T. M. Johnson, J. B. Pracyk, M. Kirby, K. Irani, P. J. Goldschmidt-Clermont, and T. Finkel. 1997. Rac1 is required for cell proliferation and G2/M progression. Biochem. J. 326:17-20.
70. Morrison, D. K., G. Heidecker, U. R. Rapp, and T. D. Copeland. 1993. Identification of the major phosphorylation sites of the Raf-1 kinase. J. Biol. Chem. 268:17309-17316.
71. Ohtsuka, T., K. Shimizu, B. Yamamori, S. Kuroda, and Y. Takai. 1996. Activation of brain B-Raf protein kinase by Rap1B small GTP-binding protein. J. Biol. Chem. 271:1258-1261.
72. Okada, T., C. D. Hu, T. G. Jin, K. Kariya, Y. Yamawaki-Kataoka, and T. Kataoka. 1999. The strength of interaction at the Raf cysteine-rich domain is a critical determinant of response of Raf to Ras family small GTPases. Mol. Cell. Biol. 19:6057-6064.
73. 1. Science 269:1270-1272.
74. mapk are required for fibroblast proliferation. Proc. Natl. Acad. Sci. USA 90:8319-8323.
75. Pastan, I. H., G. S. Johnson, and W. B. Anderson. 1975. Role of cyclic nucleotides in growth control. Annu. Rev. Biochem. 44:491-522.
76. Peraldi, P., M. Frödin, J. V. Barnier, V. Calleja, J.-S. Scimeca, C. Filloux, G. Calothy, and E. Van Obberghen. 1995. Regulation of the MAP kinase cascade in PC12 cells: B-Raf activates MEK-1 (MAP kinase or ERK kinase) and is inhibited by cAMP. FEBS Lett. 357:290-296.
77. Peterson, R. T., and S. L. Schreiber. 1999. Kinase phosphorylation: keeping it all in the family. Curr. Biol. 9:R521-R524.
78. Pham, N., I. Cheglakov, C. A. Koch, C. L. de Hoog, M. F. Moran, and D. Rotin. 2000. The guanine nucleotide exchange factor CNrasGEF activates ras in response to cAMP and cGMP. Curr. Biol. 10:555-558.
79. Pizon, V., P. Chardin, and A. Tavitian. 1990. Nucleotide sequence of a human cDNA encoding a ras-related protein (rap 1b). Nucleic Acids Res. 16:7719.
80. Polakis, P. G., B. Rubinfeld, T. Evans, and F. McCormick. 1991. Purification of a plasma membrane-assoicated GTPase-activating protein specific for rap1/Krev-1 from HL60 cells. Proc. Natl. Acad. Sci. USA 88:239-243.
81. Posern, G., C. K. Weber, U. R. Rapp, and S. M. Feller. 1998 Activity of Rap1 is regulated by bombesin, cell adhesion, and cell density in NIH3T3 fibroblasts. J. Biol. Chem. 273:24297-24300.
82. Qiu, R.-G., J. Chen, F. McCormick, and M. Symons. 1995. A role for Rho in Ras transformation. Proc. Natl. Acad. Sci. USA 92:11781-11785.
83. Qiu, W., S. Zhuang, F. C. von Lintig, G. R. Boss, and R. B. Pilz. 2000. Cell type-specific regulation of B-Raf kinase by cAMP and 14-3-3 proteins. J. Biol. Chem. 275:31921-31929.
84. Quilliam, L. A., H. Mueller, B. P. Bohl, V. Prossnitz, L. A. Sklar, C. J. Der, and G. M. Bokoch. 1991. Rap1A is a substrate for cyclic AMP-dependent protein kinase in human neutrophils. J. Immunol. 147:1628-1635.
85. Reedquist, K. A., E. Ross, E. A. Koop, R. M. Wolthuis, F. J. Zwartkruis, Y. van Kooyk, M. Salmon, C. D. Buckley, and J. L. Bos. 2000. The Small GTPase, Rap1, mediates CD31-induced integrin adhesion. J. Cell Biol. 148:1151-1158.
86. rap1. Cell 65:1033-1042.
87. Schmitt, J. M., and P. J. S. Stork. 2000. β2-adrenergic receptor activates extracellular regulated kinases (ERKs) via the small G protein Rap1 and the serine/threonine kinase B-Raf. J. Biol. Chem. 275:25342-25350.
88. Sevetson, B. R., X. Kong, and J. C. Lawrence, Jr. 1993. Increasing cAMP attenuates activation of mitogen-activated protein kinase. Proc. Natl. Acad. Sci. USA 90:10305-10309.
89. Sidovar, M. F., P. Kozlowski, J. W. Lee, M. A. Collins, Y. He, and L. M. Graves. 2000. Phosphorylation of serine 43 is not required for inhibition of C-Raf kinase by the cAMP-dependent protein kinase. J. Biol. Chem. 275: 28688-28694.
90. Stacey, D. W., L. A. Feig, and J. B. Gibbs. 1991. Dominant inhibitory Ras mutants selectively inhibit the activity of either cellular or oncogenic Ras. Mol. Cell. Biol. 11:4053-4064.
91. Stang, S., D. Bottorff, and J. C. Stone. 1997. Interaction of activated Ras with Raf-1 alone may be sufficient for transformation of Rat2 cells. Mol. Cell. Biol. 17:3047-3055.
92. Suhasini, M., H. Li, S. M. Lohmann, G. R. Boss, and R. B. Pilz. 1998. Cyclic-GMP-dependent protein kinase inhibits the Ras/mitogen-activated protein kinase pathway. Mol. Cell. Biol. 18:6983-6994.
93. S6K-independent signaling in growth factor-stimulated NIH 3T3 fibroblasts. Mol. Cell. Biol. 19:1346-1358.
94. kip1 downregulation, passage through the restriction point, and entry into S phase in growth factor-stimulated NIH 3T3 fibroblasts. Mol. Cell. Biol. 17:5348-5358.
95. Taylor, S. J., and D. Shalloway. 1996. Cell cycle-dependent activation of Ras. Curr. Biol. 6:1621-1627.
96. Tetsu, O., and F. McCormick. 1999. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398:422-426.
97. Thomas, S. M., M. DeMarco, G. D'Arcangelo, S. Halegoua, and J. S. Brugge. 1992. Ras is essential for nerve growth factor and phorbol ester-induced tyrosine phosphorylation of MAP kinases. Cell 68:1031-1040.
98. Treinies, I., H. F. Paterson, S. Hooper, R. Wilson, and C. J. Marshall. 1999. Activated MEK stimulates expression of AP-1 components independently of phosphatidylinositol 3-kinase (PI3-kinase) but requires a PI3-kinase signal to stimulate DNA synthesis. Mol. Cell. Biol. 19:321-329.
99. Tsukamoto, N., M. Hattori, H. Yang, J. L. Bos, and N. Minato. 1999. Rap1 GTPase-activating protein SPA-1 negatively regulates cell adhesion. J. Biol. Chem. 274:18463-18469.
100. Tsygankova, O. M., E. Kupperman, W. Wen, and J. L. Meinkoth. 2000. Cyclic AMP activates Ras. Oncogene 19:3609-3615.
101. Tsygankova, O. M., A. Saavedra, J. F. Rebhun, L. A. Quilliam, and J. L. Meinkoth. 2001. Coordinated regulation of Rap1 and thyroid differentiation by cyclic AMP and protein kinase A. Mol. Cell. Biol. 21:1921-1929.
102. Vaillancourt, R. R., A. M. Gardner, and G. L. Johnson. 1994. B-Raf dependent regulation of the MEK-1/MAP kinase pathway in PC12 cells and regulation by cAMP. Mol. Cell. Biol. 14:6522-6530.
103. Vojitek, A. B., S. M. Hollenberg, and J. A. Cooper. 1993. Mammalian ras interacts directly with the serine/threonine kinase raf. Cell 74:205-214.
104. von Lintig, F. C., R. B. Pilz, and G. R. Boss. 2000. Quantitative determination of Rap 1 activation in cyclic nucleotide-treated HL-60 leukemic cells: lack of Rap 1 activation in variant cells. Oncogene 19:4029-4034.
105. Vossler, M., H. Yao, R. York, C. Rim, M.-G. Pan, and P. J. S. Stork. 1997. cAMP activates MAP kinase and Elk-1 through a B-Raf-and Rap1-dependent pathway. Cell 89:73-82.
106. Wan, Y., and X. Y. Huang. 1998. Analysis of the Gs/mitogen-activated protein kinase pathway in mutant S49 cells. J. Biol. Chem. 273:14533-14537.
107. Webb, C. P., L. Van Aelst, M. H. Wigler, and G. F. Woude. 1998. Signaling pathways in Ras-mediated tumorigenicity and metastasis. Proc. Natl. Acad. Sci. USA 95:8773-8778.
108. Wilkinson, M. G., and J. B. Millar. 2000. Control of the eukaryotic cell cycle by MAP kinase signaling pathways. FASEB J. 14:2147-2157.
109. Wolthuis, R. M., B. Bauer, L. J. van't Veer, A. M. de Vries-Smits, R. H. Cool, M. Spaargaren, A. Wittinghofer, B. M. Burgering, and J. L. Bos. 1996. Ra1GDS-like factor (R1f) is a novel Ras and Rap 1A-associating protein. Oncogene 13:353-362.
110. Cip1. Mol. Cell. Biol. 17: 5598-5611.
111. Wu, J., P. Dent, T. Jelinek, A. Wolfman, M. J. Weber, and T. W. Sturgill. 1993. Inhibition of the EGF-activated MAP kinase signaling pathway by adenosine 3′, 5′-monophosphate. Science 262:1065-1068.
112. Xing, L., C. Ge, R. Zeltser, G. Maskevitch, B. J. Mayer, and K. Alexandropoulos. 2000. c-Src signaling induced by the adapters Sin and Cas is mediated by Rap1 GTPase. Mol. Cell. Biol. 20:7363-7377.
113. York, R. D., D. C. Molliver, S. S. Grewal, P. E. Stenberg, E. W. McCleskey, and P. J. Stork. 2000. Role of phosphoinositide 3-kinase and endocytosis in nerve growth factor-induced extracellular signal-regulated kinase activation via Ras and Rap1. Mol. Cell. Biol. 20:8069-8083.
114. York, R. D., H. Yao, T. Dillon, C. L. Ellig, S. P. Eckert, E. W. McCleskey, and P. J. S. Stork. 1998. Rap1 mediates sustained MAP kinase activation induced by nerve growth factor. Nature 392:622-625.
115. Yoshida, Y., M. Kawata, Y. Miura, T. Musha, T. Sasaki, A. Kikuchi, and U. Takai. 1992. Microinjection of smg/rap1/Krev-1 p21 into Swiss 3T3 cells induces DNA synthesis and morphological changes. Mol. Cell. Biol. 12: 3407-3414.
116. Yung, Y., Y. Dolginov, Z. Yao, H. Rubinfeld, D. Michael, T. Hanoch, E. Roubini, Z. Lando, D. Zharhary, and R. Seger. 1997. Detection of ERK activation by a novel monoclonal antibody. FEBS Lett. 408:292-296.
117. ras proteins bind to the amino-terminal regulatory domain of c-raf-1. Nature 364:308-313.
118. Zwartkruis, F. J., and J. L. Bos. 1999. Ras and Rap1: two highly related small GTPases with distinct function. Exp. Cell Res. 253:157-165.
119. Zwartkruis, F. J., R. M. Wolthuis, N. M. Nabben, B. Franke, and J. L. Bos. 1998. Extracellular signal-regulated activation of Rap1 fails to interfere in Ras effector signalling. EMBO J. 17:5905-5912.