This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Schmitt, J. M.
Right arrow Articles by Stork, P. J. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schmitt, J. M.
Right arrow Articles by Stork, P. J. S.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, June 2001, p. 3671-3683, Vol. 21, No. 11
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.11.3671-3683.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Cyclic AMP-Mediated Inhibition of Cell Growth Requires the Small G Protein Rap1

John M. Schmitt and Philip J. S. Stork*

Vollum Institute, Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland, Oregon 97201

Received 2 February 2001/Returned for modification 27 February 2001/Accepted 9 March 2001

In many normal and transformed cell types, the intracellular second messenger cyclic AMP (cAMP) blocks the effects of growth factors and serum on mitogenesis, proliferation, and cell cycle progression. cAMP exerts these growth-inhibitory effects via inhibition of the mitogen-activated protein (MAP) kinase cascade. Here, using Hek293 and NIH 3T3 cells, we show that cAMP's inhibition of the MAP kinase cascade is mediated by the small G protein Rap1. Activation of Rap1 by cAMP induces the association of Rap1 with Raf-1 and limits Ras-dependent activation of ERK. In NIH 3T3 cells, Rap1 is required not only for cAMP's inhibition of ERK activation but for inhibition of cell proliferation and mitogenesis as well.


* Corresponding author. Mailing address: Vollum Institute, L474, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd., Portland, OR 97201-3098 Phone: (503) 494-5494. Fax: (503) 494-4976. E-mail: stork{at}ohsu.edu.


Molecular and Cellular Biology, June 2001, p. 3671-3683, Vol. 21, No. 11
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.11.3671-3683.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.



This article has been cited by other articles:

  • Edreira, M. M., Li, S., Hochbaum, D., Wong, S., Gorfe, A. A., Ribeiro-Neto, F., Woods, V. L. Jr., Altschuler, D. L. (2009). Phosphorylation-induced Conformational Changes in Rap1b: ALLOSTERIC EFFECTS ON SWITCH DOMAINS AND EFFECTOR LOOP. J. Biol. Chem. 284: 27480-27486 [Abstract] [Full Text]  
  • Stefanini, L., Roden, R. C., Bergmeier, W. (2009). CalDAG-GEFI is at the nexus of calcium-dependent platelet activation. Blood 114: 2506-2514 [Abstract] [Full Text]  
  • Ye, X., Shobe, J. L., Sharma, S. K., Marina, A., Carew, T. J. (2008). Small G proteins exhibit pattern sensitivity in MAPK activation during the induction of memory and synaptic facilitation in Aplysia. Proc. Natl. Acad. Sci. USA 105: 20511-20516 [Abstract] [Full Text]  
  • Morton, A. M., McManus, B., Garside, P., Mowat, A. McI., Harnett, M. M. (2007). Inverse Rap1 and Phospho-ERK Expression Discriminate the Maintenance Phase of Tolerance and Priming of Antigen-Specific CD4+ T Cells In Vitro and In Vivo. J. Immunol. 179: 8026-8034 [Abstract] [Full Text]  
  • Ishida, M., Mitsui, T., Yamakawa, K., Sugiyama, N., Takahashi, W., Shimura, H., Endo, T., Kobayashi, T., Arita, J. (2007). Involvement of cAMP response element-binding protein in the regulation of cell proliferation and the prolactin promoter of lactotrophs in primary culture. Am. J. Physiol. Endocrinol. Metab. 293: E1529-E1537 [Abstract] [Full Text]  
  • Arena, S., Pattarozzi, A., Massa, A., Esteve, J.-P., Iuliano, R., Fusco, A., Susini, C., Florio, T. (2007). An Intracellular Multi-Effector Complex Mediates Somatostatin Receptor 1 Activation of Phospho-Tyrosine Phosphatase {eta}. Mol. Endocrinol. 21: 229-246 [Abstract] [Full Text]  
  • Li, J., O'Connor, K. L., Cheng, X., Mei, F. C., Uchida, T., Townsend, C. M. Jr, Evers, B. M. (2007). Cyclic Adenosine 5'-Monophosphate-Stimulated Neurotensin Secretion Is Mediated through Rap1 Downstream of both Epac and Protein Kinase A Signaling Pathways. Mol. Endocrinol. 21: 159-171 [Abstract] [Full Text]  
  • Michl, P., Knobel, B., Downward, J. (2006). CUTL1 Is Phosphorylated by Protein Kinase A, Modulating Its Effects on Cell Proliferation and Motility. J. Biol. Chem. 281: 15138-15144 [Abstract] [Full Text]  
  • Misra, U. K., Pizzo, S. V. (2005). Coordinate Regulation of Forskolin-induced Cellular Proliferation in Macrophages by Protein Kinase A/cAMP-response Element-binding Protein (CREB) and Epac1-Rap1 Signaling: EFFECTS OF SILENCING CREB GENE EXPRESSION ON Akt ACTIVATION. J. Biol. Chem. 280: 38276-38289 [Abstract] [Full Text]  
  • Stork, P. J. S., Dillon, T. J. (2005). Multiple roles of Rap1 in hematopoietic cells: complementary versus antagonistic functions. Blood 106: 2952-2961 [Abstract] [Full Text]  
  • Ahn, Y.-H., Jung, J. M., Hong, S. H. (2005). 8-Chloro-Cyclic AMP-Induced Growth Inhibition and Apoptosis Is Mediated by p38 Mitogen-Activated Protein Kinase Activation in HL60 Cells. Cancer Res. 65: 4896-4901 [Abstract] [Full Text]  
  • Ribeiro-Neto, F., Leon, A., Urbani-Brocard, J., Lou, L., Nyska, A., Altschuler, D. L. (2004). cAMP-dependent Oncogenic Action of Rap1b in the Thyroid Gland. J. Biol. Chem. 279: 46868-46875 [Abstract] [Full Text]  
  • Tiwari, S., Felekkis, K., Moon, E.-Y., Flies, A., Sherr, D. H., Lerner, A. (2004). Among circulating hematopoietic cells, B-CLL uniquely expresses functional EPAC1, but EPAC1-mediated Rap1 activation does not account for PDE4 inhibitor-induced apoptosis. Blood 103: 2661-2667 [Abstract] [Full Text]  
  • Lee, H., Rezai-Zadeh, N., Seto, E. (2004). Negative Regulation of Histone Deacetylase 8 Activity by Cyclic AMP-Dependent Protein Kinase A. Mol. Cell. Biol. 24: 765-773 [Abstract] [Full Text]  
  • Balmanno, K., Millar, T., McMahon, M., Cook, S. J. (2003). {Delta}Raf-1:ER* Bypasses the Cyclic AMP Block of Extracellular Signal-Regulated Kinase 1 and 2 Activation but Not CDK2 Activation or Cell Cycle Reentry. Mol. Cell. Biol. 23: 9303-9317 [Abstract] [Full Text]  
  • Porcellini, A., Messina, S., De Gregorio, G., Feliciello, A., Carlucci, A., Barone, M., Picascia, A., De Blasi, A., Avvedimento, E. V. (2003). The Expression of the Thyroid-stimulating Hormone (TSH) Receptor and the cAMP-dependent Protein Kinase RII {beta} Regulatory Subunit Confers TSH-cAMP-dependent Growth to Mouse Fibroblasts. J. Biol. Chem. 278: 40621-40630 [Abstract] [Full Text]  
  • Lee, H. T., Kay, E. P. (2003). Regulatory Role of cAMP on Expression of Cdk4 and p27Kip1 by Inhibiting Phosphatidylinositol 3-kinase in Corneal Endothelial Cells. IOVS 44: 3816-3825 [Abstract] [Full Text]  
  • Ferjoux, G., Lopez, F., Esteve, J.-P., Ferrand, A., Vivier, E., Vely, F., Saint-Laurent, N., Pradayrol, L., Buscail, L., Susini, C. (2003). Critical Role of Src and SHP-2 in sst2 Somatostatin Receptor-mediated Activation of SHP-1 and Inhibition of Cell Proliferation. Mol. Biol. Cell 14: 3911-3928 [Abstract] [Full Text]  
  • Pissios, P., Trombly, D. J., Tzameli, I., Maratos-Flier, E. (2003). Melanin-Concentrating Hormone Receptor 1 Activates Extracellular Signal-Regulated Kinase and Synergizes with Gs-Coupled Pathways. Endocrinology 144: 3514-3523 [Abstract] [Full Text]  
  • Habib, S. L., Phan, M. N., Patel, S. K., Li, D., Monks, T. J., Lau, S. S. (2003). Reduced constitutive 8-oxoguanine-DNA glycosylase expression and impaired induction following oxidative DNA damage in the tuberin deficient Eker rat. Carcinogenesis 24: 573-582 [Abstract] [Full Text]  
  • Caron, E. (2003). Cellular functions of the Rap1 GTP-binding protein: a pattern emerges. J. Cell Sci. 116: 435-440 [Abstract] [Full Text]  
  • Grader-Beck, T., van Puijenbroek, A. A. F. L., Nadler, L. M., Boussiotis, V. A. (2003). cAMP inhibits both Ras and Rap1 activation in primary human T lymphocytes, but only Ras inhibition correlates with blockade of cell cycle progression. Blood 101: 998-1006 [Abstract] [Full Text]  
  • Gendron, L., Oligny, J.-F., Payet, M. D., Gallo-Payet, N. (2003). Cyclic AMP-independent Involvement of Rap1/B-Raf in the Angiotensin II AT2 Receptor Signaling Pathway in NG108-15 Cells. J. Biol. Chem. 278: 3606-3614 [Abstract] [Full Text]  
  • Carey, K. D., Watson, R. T., Pessin, J. E., Stork, P. J. S. (2003). The Requirement of Specific Membrane Domains for Raf-1 Phosphorylation and Activation. J. Biol. Chem. 278: 3185-3196 [Abstract] [Full Text]  
  • Gomez, E., Pritchard, C., Herbert, T. P. (2002). cAMP-dependent Protein Kinase and Ca2+ Influx through L-type Voltage-gated Calcium Channels Mediate Raf-independent Activation of Extracellular Regulated Kinase in Response to Glucagon-like Peptide-1 in Pancreatic beta -Cells. J. Biol. Chem. 277: 48146-48151 [Abstract] [Full Text]  
  • Schmitt, J. M., Stork, P. J. S. (2002). Galpha and Gbeta gamma Require Distinct Src-dependent Pathways to Activate Rap1 and Ras. J. Biol. Chem. 277: 43024-43032 [Abstract] [Full Text]  
  • Meng, J., Casey, P. J. (2002). Activation of Gz Attenuates Rap1-mediated Differentiation of PC12 Cells. J. Biol. Chem. 277: 43417-43424 [Abstract] [Full Text]  
  • Lou, L., Urbani, J., Ribeiro-Neto, F., Altschuler, D. L. (2002). cAMP Inhibition of Akt Is Mediated by Activated and Phosphorylated Rap1b. J. Biol. Chem. 277: 32799-32806 [Abstract] [Full Text]  
  • Steinberg, S. F. (2002). Focus on "Targeted expression of activated Q227L Galpha s in vivo". Am. J. Physiol. Cell Physiol. 283: C383-C385 [Full Text]  
  • Ribeiro-Neto, F., Urbani, J., Lemee, N., Lou, L., Altschuler, D. L. (2002). On the mitogenic properties of Rap1b: cAMP-induced G1/S entry requires activated and phosphorylated Rap1b. Proc. Natl. Acad. Sci. USA 99: 5418-5423 [Abstract] [Full Text]  
  • Wang, L., Liu, F., Adamo, M. L. (2001). Cyclic AMP Inhibits Extracellular Signal-regulated Kinase and Phosphatidylinositol 3-Kinase/Akt Pathways by Inhibiting Rap1. J. Biol. Chem. 276: 37242-37249 [Abstract] [Full Text]