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 Tognon, C. E.
Right arrow Articles by Kay, R. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tognon, C. E.
Right arrow Articles by Kay, R. J.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, December 1998, p. 6995-7008, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Regulation of RasGRP via a Phorbol Ester-Responsive C1 Domain

Cristina E. Tognon,1,2 Heather E. Kirk,1,2 Lori A. Passmore,1 Ian P. Whitehead,3 Channing J. Der,3 and Robert J. Kay1,2,*

Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada V5Z 4E61; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z32; and Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 275993

Received 21 April 1998/Returned for modification 1 July 1998/Accepted 21 August 1998

As part of a cDNA library screen for clones that induce transformation of NIH 3T3 fibroblasts, we have isolated a cDNA encoding the murine homolog of the guanine nucleotide exchange factor RasGRP. A point mutation predicted to prevent interaction with Ras abolished the ability of murine RasGRP (mRasGRP) to transform fibroblasts and to activate mitogen-activated protein kinases (MAP kinases). MAP kinase activation via mRasGRP was enhanced by coexpression of H-, K-, and N-Ras and was partially suppressed by coexpression of dominant negative forms of H- and K-Ras. The C terminus of mRasGRP contains a pair of EF hands and a C1 domain which is very similar to the phorbol ester- and diacylglycerol-binding C1 domains of protein kinase Cs. The EF hands could be deleted without affecting the ability of mRasGRP to transform NIH 3T3 cells. In contrast, deletion of the C1 domain or an adjacent cluster of basic amino acids eliminated the transforming activity of mRasGRP. Transformation and MAP kinase activation via mRasGRP were restored if the deleted C1 domain was replaced either by a membrane-localizing prenylation signal or by a diacylglycerol- and phorbol ester-binding C1 domain of protein kinase C. The transforming activity of mRasGRP could be regulated by phorbol ester when serum concentrations were low, and this effect of phorbol ester was dependent on the C1 domain of mRasGRP. The C1 domain could also confer phorbol myristate acetate-regulated transforming activity on a prenylation-defective mutant of K-Ras. The C1 domain mediated the translocation of mRasGRP to cell membranes in response to either phorbol ester or serum stimulation. These results suggest that the primary mechanism of activation of mRasGRP in fibroblasts is through its recruitment to diacylglycerol-enriched membranes. mRasGRP is expressed in lymphoid tissues and the brain, as well as in some lymphoid cell lines. In these cells, RasGRP has the potential to serve as a direct link between receptors which stimulate diacylglycerol-generating phospholipase Cs and the activation of Ras.

* Corresponding author. Mailing address: Terry Fox Laboratory, BC Cancer Agency, 600 West 10th Ave., Vancouver, BC, Canada V5Z 4E6. Phone: (604) 877-6070. Fax: (604) 877-0712. E-mail: robert{at}terryfox.ubc.ca.

Molecular and Cellular Biology, December 1998, p. 6995-7008, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Liu, W., Wei, Y., Sun, P., Wang, W.-H., Kleyman, T. R., Satlin, L. M. (2009). Mechanoregulation of BK channel activity in the mammalian cortical collecting duct: role of protein kinases A and C. Am. J. Physiol. Renal Physiol. 297: F904-F915 [Abstract] [Full Text]  
  • Raponi, M., Lancet, J. E., Fan, H., Dossey, L., Lee, G., Gojo, I., Feldman, E. J., Gotlib, J., Morris, L. E., Greenberg, P. L., Wright, J. J., Harousseau, J.-L., Lowenberg, B., Stone, R. M., De Porre, P., Wang, Y., Karp, J. E. (2008). A 2-gene classifier for predicting response to the farnesyltransferase inhibitor tipifarnib in acute myeloid leukemia. Blood 111: 2589-2596 [Abstract] [Full Text]  
  • Ruiz, S., Santos, E., Bustelo, X. R. (2007). RasGRF2, a Guanosine Nucleotide Exchange Factor for Ras GTPases, Participates in T-Cell Signaling Responses. Mol. Cell. Biol. 27: 8127-8142 [Abstract] [Full Text]  
  • Beaulieu, N., Zahedi, B., Goulding, R. E., Tazmini, G., Anthony, K. V., Omeis, S. L., de Jong, D. R., Kay, R. J. (2007). Regulation of RasGRP1 by B Cell Antigen Receptor Requires Cooperativity between Three Domains Controlling Translocation to the Plasma Membrane. Mol. Biol. Cell 18: 3156-3168 [Abstract] [Full Text]  
  • Han, S., Knoepp, S. M., Hallman, M. A., Meier, K. E. (2007). RasGRP1 Confers the Phorbol Ester-Sensitive Phenotype to EL4 Lymphoma Cells. Mol. Pharmacol. 71: 314-322 [Abstract] [Full Text]  
  • Yamaguchi, Y., Shirai, Y., Matsubara, T., Sanse, K., Kuriyama, M., Oshiro, N., Yoshino, K.-i., Yonezawa, K., Ono, Y., Saito, N. (2006). Phosphorylation and Up-regulation of Diacylglycerol Kinase {gamma} via Its Interaction with Protein Kinase C{gamma}. J. Biol. Chem. 281: 31627-31637 [Abstract] [Full Text]  
  • Priatel, J. J., Chen, X., Dhanji, S., Abraham, N., Teh, H.-S. (2006). RasGRP1 Transmits Prodifferentiation TCR Signaling That Is Crucial for CD4 T Cell Development. J. Immunol. 177: 1470-1480 [Abstract] [Full Text]  
  • Zhou, F., Hu, J., Ma, H., Harrison, M. L., Geahlen, R. L. (2006). Nucleocytoplasmic trafficking of the syk protein tyrosine kinase.. Mol. Cell. Biol. 26: 3478-3491 [Abstract] [Full Text]  
  • Tuthill, M. C., Oki, C. E., Lorenzo, P. S. (2006). Differential effects of bryostatin 1 and 12-O-tetradecanoylphorbol-13-acetate on the regulation and activation of RasGRP1 in mouse epidermal keratinocytes.. Molecular Cancer Therapeutics 5: 602-610 [Abstract] [Full Text]  
  • Wabnitz, G. H., Nebl, G., Klemke, M., Schroder, A. J., Samstag, Y. (2006). Phosphatidylinositol 3-Kinase Functions as a Ras Effector in the Signaling Cascade That Regulates Dephosphorylation of the Actin-Remodeling Protein Cofilin after Costimulation of Untransformed Human T Lymphocytes. J. Immunol. 176: 1668-1674 [Abstract] [Full Text]  
  • Coughlin, J. J., Stang, S. L., Dower, N. A., Stone, J. C. (2005). RasGRP1 and RasGRP3 Regulate B Cell Proliferation by Facilitating B Cell Receptor-Ras Signaling. J. Immunol. 175: 7179-7184 [Abstract] [Full Text]  
  • Pu, Y., Perry, N. A., Yang, D., Lewin, N. E., Kedei, N., Braun, D. C., Choi, S. H., Blumberg, P. M., Garfield, S. H., Stone, J. C., Duan, D., Marquez, V. E. (2005). A Novel Diacylglycerol-lactone Shows Marked Selectivity in Vitro among C1 Domains of Protein Kinase C (PKC) Isoforms {alpha} and {delta} as Well as Selectivity for RasGRP Compared with PKC{alpha}. J. Biol. Chem. 280: 27329-27338 [Abstract] [Full Text]  
  • Kupzig, S., Walker, S. A., Cullen, P. J. (2005). The frequencies of calcium oscillations are optimized for efficient calcium-mediated activation of Ras and the ERK/MAPK cascade. Proc. Natl. Acad. Sci. USA 102: 7577-7582 [Abstract] [Full Text]  
  • Zheng, Y., Liu, H., Coughlin, J., Zheng, J., Li, L., Stone, J. C. (2005). Phosphorylation of RasGRP3 on threonine 133 provides a mechanistic link between PKC and Ras signaling systems in B cells. Blood 105: 3648-3654 [Abstract] [Full Text]  
  • Roberts, D. M., Anderson, A. L., Hidaka, M., Swetenburg, R. L., Patterson, C., Stanford, W. L., Bautch, V. L. (2004). A Vascular Gene Trap Screen Defines RasGRP3 as an Angiogenesis-Regulated Gene Required for the Endothelial Response to Phorbol Esters. Mol. Cell. Biol. 24: 10515-10528 [Abstract] [Full Text]  
  • Deutsch, E., Cohen, A., Kazimirsky, G., Dovrat, S., Rubinfeld, H., Brodie, C., Sarid, R. (2004). Role of Protein Kinase C {delta} in Reactivation of Kaposi's Sarcoma-Associated Herpesvirus. J. Virol. 78: 10187-10192 [Abstract] [Full Text]  
  • Anglesio, M. S., Evdokimova, V., Melnyk, N., Zhang, L., Fernandez, C. V., Grundy, P. E., Leach, S., Marra, M. A., Brooks-Wilson, A. R., Penninger, J., Sorensen, P. H.B. (2004). Differential expression of a novel ankyrin containing E3 ubiquitin-protein ligase, Hace1, in sporadic Wilms' tumor versus normal kidney. Hum Mol Genet 13: 2061-2074 [Abstract] [Full Text]  
  • Guilbault, B., Kay, R. J. (2004). RasGRP1 Sensitizes an Immature B Cell Line to Antigen Receptor-induced Apoptosis. J. Biol. Chem. 279: 19523-19530 [Abstract] [Full Text]  
  • Caloca, M. J., Zugaza, J. L., Vicente-Manzanares, M., Sanchez-Madrid, F., Bustelo, X. R. (2004). F-actin-dependent Translocation of the Rap1 GDP/GTP Exchange Factor RasGRP2. J. Biol. Chem. 279: 20435-20446 [Abstract] [Full Text]  
  • Reynolds, L. F., de Bettignies, C., Norton, T., Beeser, A., Chernoff, J., Tybulewicz, V. L. J. (2004). Vav1 Transduces T Cell Receptor Signals to the Activation of the Ras/ERK Pathway via LAT, Sos, and RasGRP1. J. Biol. Chem. 279: 18239-18246 [Abstract] [Full Text]  
  • Wen, B. G., Pletcher, M. T., Warashina, M., Choe, S. H., Ziaee, N., Wiltshire, T., Sauer, K., Cooke, M. P. (2004). Inositol (1,4,5) trisphosphate 3 kinase B controls positive selection of T cells and modulates Erk activity. Proc. Natl. Acad. Sci. USA 101: 5604-5609 [Abstract] [Full Text]  
  • Ishiguro, K., Xavier, R. (2004). Homer-3 regulates activation of serum response element in T cells via its EVH1 domain. Blood 103: 2248-2256 [Abstract] [Full Text]  
  • Gomez-Merino, F. C., Brearley, C. A., Ornatowska, M., Abdel-Haliem, M. E. F., Zanor, M.-I., Mueller-Roeber, B. (2004). AtDGK2, a Novel Diacylglycerol Kinase from Arabidopsis thaliana, Phosphorylates 1-Stearoyl-2-arachidonoyl-sn-glycerol and 1,2-Dioleoyl-sn-glycerol and Exhibits Cold-inducible Gene Expression. J. Biol. Chem. 279: 8230-8241 [Abstract] [Full Text]  
  • Madani, S., Hichami, A., Charkaoui-Malki, M., Khan, N. A. (2004). Diacylglycerols Containing Omega 3 and Omega 6 Fatty Acids Bind to RasGRP and Modulate MAP Kinase Activation. J. Biol. Chem. 279: 1176-1183 [Abstract] [Full Text]  
  • Rambaratsingh, R. A., Stone, J. C., Blumberg, P. M., Lorenzo, P. S. (2003). RasGRP1 Represents a Novel Non-protein Kinase C Phorbol Ester Signaling Pathway in Mouse Epidermal Keratinocytes. J. Biol. Chem. 278: 52792-52801 [Abstract] [Full Text]  
  • Oh-hora, M., Johmura, S., Hashimoto, A., Hikida, M., Kurosaki, T. (2003). Requirement for Ras Guanine Nucleotide Releasing Protein 3 in Coupling Phospholipase C-{gamma}2 to Ras in B Cell Receptor Signaling. JEM 198: 1841-1851 [Abstract] [Full Text]  
  • Teixeira, C., Stang, S. L., Zheng, Y., Beswick, N. S., Stone, J. C. (2003). Integration of DAG signaling systems mediated by PKC-dependent phosphorylation of RasGRP3. Blood 102: 1414-1420 [Abstract] [Full Text]  
  • Tabuchi, A., Yoshioka, A., Higashi, T., Shirakawa, R., Nishioka, H., Kita, T., Horiuchi, H. (2003). Direct Demonstration of Involvement of Protein Kinase C{alpha} in the Ca2+-induced Platelet Aggregation. J. Biol. Chem. 278: 26374-26379 [Abstract] [Full Text]  
  • Li, L., Yang, Y., Wong, G. W., Stevens, R. L. (2003). Mast Cells in Airway Hyporesponsive C3H/HeJ Mice Express a Unique Isoform of the Signaling Protein Ras Guanine Nucleotide Releasing Protein 4 That Is Unresponsive to Diacylglycerol and Phorbol Esters. J. Immunol. 171: 390-397 [Abstract] [Full Text]  
  • Kang, M.-A., Yun, S.-Y., Won, J. (2003). Rosmarinic acid inhibits Ca2+-dependent pathways of T-cell antigen receptor-mediated signaling by inhibiting the PLC-gamma 1 and Itk activity. Blood 101: 3534-3542 [Abstract] [Full Text]  
  • Norment, A. M., Bogatzki, L. Y., Klinger, M., Ojala, E. W., Bevan, M. J., Kay, R. J. (2003). Transgenic Expression of RasGRP1 Induces the Maturation of Double-Negative Thymocytes and Enhances the Production of CD8 Single-Positive Thymocytes. J. Immunol. 170: 1141-1149 [Abstract] [Full Text]  
  • Palmby, T. R., Abe, K., Der, C. J. (2002). Critical Role of the Pleckstrin Homology and Cysteine-rich Domains in Vav Signaling and Transforming Activity. J. Biol. Chem. 277: 39350-39359 [Abstract] [Full Text]  
  • Reuther, G. W., Lambert, Q. T., Rebhun, J. F., Caligiuri, M. A., Quilliam, L. A., Der, C. J. (2002). RasGRP4 Is a Novel Ras Activator Isolated from Acute Myeloid Leukemia. J. Biol. Chem. 277: 30508-30514 [Abstract] [Full Text]  
  • Zhong, X.-P., Hainey, E. A., Olenchock, B. A., Zhao, H., Topham, M. K., Koretzky, G. A. (2002). Regulation of T Cell Receptor-induced Activation of the Ras-ERK Pathway by Diacylglycerol Kinase zeta. J. Biol. Chem. 277: 31089-31098 [Abstract] [Full Text]  
  • Yang, Y., Li, L., Wong, G. W., Krilis, S. A., Madhusudhan, M. S., Sali, A., Stevens, R. L. (2002). RasGRP4, a New Mast Cell-restricted Ras Guanine Nucleotide-releasing Protein with Calcium- and Diacylglycerol-binding Motifs. IDENTIFICATION OF DEFECTIVE VARIANTS OF THIS SIGNALING PROTEIN IN ASTHMA, MASTOCYTOSIS, AND MAST CELL LEUKEMIA PATIENTS AND DEMONSTRATION OF THE IMPORTANCE OF RasGRP4 IN MAST CELL DEVELOPMENT AND FUNCTION. J. Biol. Chem. 277: 25756-25774 [Abstract] [Full Text]  
  • Fernandez-Medarde, A., Esteban, L. M., Nunez, A., Porteros, A., Tessarollo, L., Santos, E. (2002). Targeted Disruption of Ras-Grf2 Shows Its Dispensability for Mouse Growth and Development. Mol. Cell. Biol. 22: 2498-2504 [Abstract] [Full Text]  
  • Kazanietz, M. G. (2002). Novel "Nonkinase" Phorbol Ester Receptors: The C1 Domain Connection. Mol. Pharmacol. 61: 759-767 [Abstract] [Full Text]  
  • Eichhorn, J., Kayali, A. G., Resor, L., Austin, D. A., Rose, D. W., Webster, N. J. G. (2002). PLC-{gamma}1 Enzyme Activity Is Required for Insulin-Induced DNA Synthesis. Endocrinology 143: 655-664 [Abstract] [Full Text]  
  • Brose, N., Rosenmund, C. (2002). Move over protein kinase C, you've got company: alternative cellular effectors of diacylglycerol and phorbol esters. J. Cell Sci. 115: 4399-4411 [Abstract] [Full Text]  
  • Shan, X., Balakir, R., Criado, G., Wood, J. S., Seminario, M.-C., Madrenas, J., Wange, R. L. (2001). ZAP-70-Independent Ca2+ Mobilization and Erk Activation in Jurkat T Cells in Response to T-Cell Antigen Receptor Ligation. Mol. Cell. Biol. 21: 7137-7149 [Abstract] [Full Text]  
  • Topham, M. K., Prescott, S. M. (2001). Diacylglycerol Kinase {zeta} Regulates Ras Activation by a Novel Mechanism. JCB 152: 1135-1144 [Abstract] [Full Text]  
  • Lorenzo, P. S., Kung, J. W., Bottorff, D. A., Garfield, S. H., Stone, J. C., Blumberg, P. M. (2001). Phorbol Esters Modulate the Ras Exchange Factor RasGRP3. Cancer Res. 61: 943-949 [Abstract] [Full Text]  
  • Puente, L. G., Stone, J. C., Ostergaard, H. L. (2000). Evidence for Protein Kinase C-Dependent and -Independent Activation of Mitogen-Activated Protein Kinase in T Cells: Potential Role of Additional Diacylglycerol Binding Proteins. J. Immunol. 165: 6865-6871 [Abstract] [Full Text]  
  • Reuther, G. W., Lambert, Q. T., Caligiuri, M. A., Der, C. J. (2000). Identification and Characterization of an Activating TrkA Deletion Mutation in Acute Myeloid Leukemia. Mol. Cell. Biol. 20: 8655-8666 [Abstract] [Full Text]  
  • Ebinu, J. O., Stang, S. L., Teixeira, C., Bottorff, D. A., Hooton, J., Blumberg, P. M., Barry, M., Bleakley, R. C., Ostergaard, H. L., Stone, J. C. (2000). RasGRP links T-cell receptor signaling to Ras. Blood 95: 3199-3203 [Abstract] [Full Text]  
  • Lorenzo, P. S., Beheshti, M., Pettit, G. R., Stone, J. C., Blumberg, P. M. (2000). The Guanine Nucleotide Exchange Factor RasGRP Is a High -Affinity Target for Diacylglycerol and Phorbol Esters. Mol. Pharmacol. 57: 840-846 [Abstract] [Full Text]  
  • Apolloni, A., Prior, I. A., Lindsay, M., Parton, R. G., Hancock, J. F. (2000). H-ras but Not K-ras Traffics to the Plasma Membrane through the Exocytic Pathway. Mol. Cell. Biol. 20: 2475-2487 [Abstract] [Full Text]  
  • Kiyono, M., Kaziro, Y., Satoh, T. (2000). Induction of Rac-Guanine Nucleotide Exchange Activity of Ras-GRF1/CDC25Mm following Phosphorylation by the Nonreceptor Tyrosine Kinase Src. J. Biol. Chem. 275: 5441-5446 [Abstract] [Full Text]  
  • RON, D., KAZANIETZ, M. G. (1999). New insights into the regulation of protein kinase C and novel phorbol ester receptors. FASEB J. 13: 1658-1676 [Abstract] [Full Text]  
  • M'Rabet, L., Coffer, P. J., Wolthuis, R. M. F., Zwartkruis, F., Koenderman, L., Bos, J. L. (1999). Differential fMet-Leu-Phe- and Platelet-activating Factor-induced Signaling Toward Ral Activation in Primary Human Neutrophils. J. Biol. Chem. 274: 21847-21852 [Abstract] [Full Text]  
  • Chiloeches, A., Paterson, H. F., Marais, R., Clerk, A., Marshall, C. J., Sugden, P. H. (1999). Regulation of Ras{middle dot}GTP Loading and Ras-Raf Association in Neonatal Rat Ventricular Myocytes by G Protein-coupled Receptor Agonists and Phorbol Ester. ACTIVATION OF THE EXTRACELLULAR SIGNAL-REGULATED KINASE CASCADE BY PHORBOL ESTER IS MEDIATED BY Ras. J. Biol. Chem. 274: 19762-19770 [Abstract] [Full Text]  
  • Anborgh, P. H., Qian, X., Papageorge, A. G., Vass, W. C., DeClue, J. E., Lowy, D. R. (1999). Ras-Specific Exchange Factor GRF: Oligomerization through Its Dbl Homology Domain and Calcium-Dependent Activation of Raf. Mol. Cell. Biol. 19: 4611-4622 [Abstract] [Full Text]  
  • Ohba, Y., Mochizuki, N., Yamashita, S., Chan, A. M., Schrader, J. W., Hattori, S., Nagashima, K., Matsuda, M. (2000). Regulatory Proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3. J. Biol. Chem. 275: 20020-20026 [Abstract] [Full Text]  
  • Rebhun, J. F., Castro, A. F., Quilliam, L. A. (2000). Identification of Guanine Nucleotide Exchange Factors (GEFs) for the Rap1 GTPase. REGULATION OF MR-GEF BY M-Ras-GTP INTERACTION. J. Biol. Chem. 275: 34901-34908 [Abstract] [Full Text]  
  • Baouz, S., Jacquet, E., Accorsi, K., Hountondji, C., Balestrini, M., Zippel, R., Sturani, E., Parmeggiani, A. (2001). Sites of Phosphorylation by Protein Kinase A in CDC25Mm/GRF1, a Guanine Nucleotide Exchange Factor for Ras. J. Biol. Chem. 276: 1742-1749 [Abstract] [Full Text]  
  • Clyde-Smith, J., Silins, G., Gartside, M., Grimmond, S., Etheridge, M., Apolloni, A., Hayward, N., Hancock, J. F. (2000). Characterization of RasGRP2, a Plasma Membrane-targeted, Dual Specificity Ras/Rap Exchange Factor. J. Biol. Chem. 275: 32260-32267 [Abstract] [Full Text]  
  • Dupuy, A. J., Morgan, K., von Lintig, F. C., Shen, H., Acar, H., Hasz, D. E., Jenkins, N. A., Copeland, N. G., Boss, G. R., Largaespada, D. A. (2001). Activation of the Rap1 Guanine Nucleotide Exchange Gene, CalDAG-GEF I, in BXH-2 Murine Myeloid Leukemia. J. Biol. Chem. 276: 11804-11811 [Abstract] [Full Text]  
  • Ingham, R. J., Santos, L., Dang-Lawson, M., Holgado-Madruga, M., Dudek, P., Maroun, C. R., Wong, A. J., Matsuuchi, L., Gold, M. R. (2001). The Gab1 Docking Protein Links the B Cell Antigen Receptor to the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway and to the SHP2 Tyrosine Phosphatase. J. Biol. Chem. 276: 12257-12265 [Abstract] [Full Text]  
  • Cho, W. (2001). Membrane Targeting by C1 and C2 Domains. J. Biol. Chem. 276: 32407-32410 [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»