This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Eisenmann, K. M. Articles by Koo, H.-M. Search for Related Content PubMed PubMed Citation Articles by Eisenmann, K. M. Articles by Koo, H.-M.

Mitogen-Activated Protein Kinase Pathway-Dependent Tumor-Specific Survival Signaling in Melanoma Cells through Inactivation of the Proapoptotic Protein Bad

Laboratory of Cancer Pharmacogenetics, Van Andel Research Institute, Grand Rapids, Michigan

Mitogen-activated protein kinase (MAPK) signaling regulates fundamental cellular functions including proliferation, differentiation, and survival. We have demonstrated previously that inhibiting MAPK signaling induces apoptosis in melanoma cells but not in normal melanocytes, suggesting that the MAPK pathway propagates essential survival signals in melanoma cells. Here, we report that the 90-kDa ribosomal S6 kinase (RSK), a downstream effector in the MAPK signaling cascade, phosphorylates and inactivates the Bcl-2 homology 3-only proapoptotic protein Bad, thereby mediating a MAPK-dependent tumor-specific survival signal in melanoma cells. The MAPK kinase (MEK)/extracellular signal-regulated kinase (ERK)/RSK MAPK signaling module is constitutively hyperactivated, and Bad is maintained in its inactive state by phosphorylation at Ser⁷⁵ in a MEK/ERK/RSK-dependent manner in melanoma cells. In contrast, in normal melanocytes, Bad is highly phosphorylated at multiple residues (Ser⁷⁵, Ser⁹⁹, and Ser¹¹⁸) in a MAPK pathway-independent manner. Importantly, ectopic expression of a constitutively activated RSK mutant abrogates Bad activation and renders melanoma cells resistant to apoptosis induced by a MEK inhibitor. Furthermore, overexpressing alanine-substituted (S75A) Bad further sensitizes melanoma cells to MEK inhibitor-induced apoptosis. Our results suggest that the MAPK pathway mediates melanoma-specific survival signaling by differentially regulating RSK-mediated phosphorylation of the proapoptotic protein Bad and may present potentially selective therapeutic targets for the treatment of melanomas.

This article has been cited by other articles:

				M. D. Larrea, F. Hong, S. A. Wander, T. G. da Silva, D. Helfman, D. Lannigan, J. A. Smith, and J. M. Slingerland RSK1 drives p27Kip1 phosphorylation at T198 to promote RhoA inhibition and increase cell motility PNAS, June 9, 2009; 106(23): 9268 - 9273. [Abstract] [Full Text] [PDF]

				M. W. VanBrocklin, M. Verhaegen, M. S. Soengas, and S. L. Holmen Mitogen-Activated Protein Kinase Inhibition Induces Translocation of Bmf to Promote Apoptosis in Melanoma Cancer Res., March 1, 2009; 69(5): 1985 - 1994. [Abstract] [Full Text] [PDF]

				K.-W. Lee, S. G. Kim, H.-P. Kim, E. Kwon, J. You, H.-J. Choi, J.-H. Park, B.-C. Kang, S.-A. Im, T.-Y. Kim, et al. Enzastaurin, a Protein Kinase C{beta} Inhibitor, Suppresses Signaling through the Ribosomal S6 Kinase and Bad Pathways and Induces Apoptosis in Human Gastric Cancer Cells Cancer Res., March 15, 2008; 68(6): 1916 - 1926. [Abstract] [Full Text] [PDF]

				Y.-H. Liao, S.-M. Hsu, and P.-H. Huang ARMS Depletion Facilitates UV Irradiation Induced Apoptotic Cell Death in Melanoma Cancer Res., December 15, 2007; 67(24): 11547 - 11556. [Abstract] [Full Text] [PDF]

				C. C. Jiang, L. H. Chen, S. Gillespie, Y. F. Wang, K. A. Kiejda, X. D. Zhang, and P. Hersey Inhibition of MEK Sensitizes Human Melanoma Cells to Endoplasmic Reticulum Stress-Induced Apoptosis Cancer Res., October 15, 2007; 67(20): 9750 - 9761. [Abstract] [Full Text] [PDF]

				Y. F. Wang, C. C. Jiang, K. A. Kiejda, S. Gillespie, X. D. Zhang, and P. Hersey Apoptosis Induction in Human Melanoma Cells by Inhibition of MEK Is Caspase-Independent and Mediated by the Bcl-2 Family Members PUMA, Bim, and Mcl-1 Clin. Cancer Res., August 15, 2007; 13(16): 4934 - 4942. [Abstract] [Full Text] [PDF]

				Y. C. Henderson, M. J. Fredrick, and G. L. Clayman Differential Responses of Human Papillary Thyroid Cancer Cell Lines Carrying the RET/PTC1 Rearrangement or a BRAF Mutation to MEK1/2 Inhibitors Arch Otolaryngol Head Neck Surg, August 1, 2007; 133(8): 810 - 815. [Abstract] [Full Text] [PDF]

				B. R. Davies, A. Logie, J. S. McKay, P. Martin, S. Steele, R. Jenkins, M. Cockerill, S. Cartlidge, and P. D. Smith AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models Mol. Cancer Ther., August 1, 2007; 6(8): 2209 - 2219. [Abstract] [Full Text] [PDF]

				B. Escudier, N. Lassau, E. Angevin, J. C. Soria, L. Chami, M. Lamuraglia, E. Zafarana, V. Landreau, B. Schwartz, E. Brendel, et al. Phase I Trial of Sorafenib in Combination with IFN {alpha}-2a in Patients with Unresectable and/or Metastatic Renal Cell Carcinoma or Malignant Melanoma Clin. Cancer Res., March 15, 2007; 13(6): 1801 - 1809. [Abstract] [Full Text] [PDF]

				G. Kroemer, L. Galluzzi, and C. Brenner Mitochondrial Membrane Permeabilization in Cell Death Physiol Rev, January 1, 2007; 87(1): 99 - 163. [Abstract] [Full Text] [PDF]

				M. Verhaegen, J. A. Bauer, C. Martin de la Vega, G. Wang, K. G. Wolter, J. C. Brenner, Z. Nikolovska-Coleska, A. Bengtson, R. Nair, J. T. Elder, et al. A Novel BH3 Mimetic Reveals a Mitogen-Activated Protein Kinase-Dependent Mechanism of Melanoma Cell Death Controlled by p53 and Reactive Oxygen Species Cancer Res., December 1, 2006; 66(23): 11348 - 11359. [Abstract] [Full Text] [PDF]

				A. J. Robinson-White, W. W. Leitner, E. Aleem, P. Kaldis, I. Bossis, and C. A. Stratakis PRKAR1A Inactivation Leads to Increased Proliferation and Decreased Apoptosis in Human B Lymphocytes Cancer Res., November 1, 2006; 66(21): 10603 - 10612. [Abstract] [Full Text] [PDF]

				M. Kono, I. S. Dunn, P. J. Durda, D. Butera, L. B. Rose, T. J. Haggerty, E. M. Benson, and J. T. Kurnick Role of the Mitogen-Activated Protein Kinase Signaling Pathway in the Regulation of Human Melanocytic Antigen Expression Mol. Cancer Res., October 1, 2006; 4(10): 779 - 792. [Abstract] [Full Text] [PDF]

				D. C. Birle and D. W. Hedley Signaling interactions of rapamycin combined with erlotinib in cervical carcinoma xenografts. Mol. Cancer Ther., October 1, 2006; 5(10): 2494 - 2502. [Abstract] [Full Text] [PDF]

				L. Chin, L. A. Garraway, and D. E. Fisher Malignant melanoma: genetics and therapeutics in the genomic era. Genes & Dev., August 15, 2006; 20(16): 2149 - 2182. [Abstract] [Full Text] [PDF]

				W. Jia, V. L. Hegde, N. P. Singh, D. Sisco, S. Grant, M. Nagarkatti, and P. S. Nagarkatti {Delta}9-Tetrahydrocannabinol-Induced Apoptosis in Jurkat Leukemia T Cells Is Regulated by Translocation of Bad to Mitochondria Mol. Cancer Res., August 1, 2006; 4(8): 549 - 562. [Abstract] [Full Text] [PDF]

				K. N. McFarland, S. R. Wilkes, S. E. Koss, K. S. Ravichandran, and J. W. Mandell Neural-specific inactivation of ShcA results in increased embryonic neural progenitor apoptosis and microencephaly. J. Neurosci., July 26, 2006; 26(30): 7885 - 7897. [Abstract] [Full Text] [PDF]

				U. K. Misra, R. Deedwania, and S. V. Pizzo Activation and Cross-talk between Akt, NF-{kappa}B, and Unfolded Protein Response Signaling in 1-LN Prostate Cancer Cells Consequent to Ligation of Cell Surface-associated GRP78 J. Biol. Chem., May 12, 2006; 281(19): 13694 - 13707. [Abstract] [Full Text] [PDF]

				D. J. Panka, M. B. Atkins, and J. W. Mier Targeting the mitogen-activated protein kinase pathway in the treatment of malignant melanoma. Clin. Cancer Res., April 1, 2006; 12(7): 2371s - 2375s. [Abstract] [Full Text] [PDF]

				D. J. Panka, W. Wang, M. B. Atkins, and J. W. Mier The Raf Inhibitor BAY 43-9006 (Sorafenib) Induces Caspase-Independent Apoptosis in Melanoma Cells Cancer Res., February 1, 2006; 66(3): 1611 - 1619. [Abstract] [Full Text] [PDF]

				S. S. Sridhar, D. Hedley, and L. L. Siu Raf kinase as a target for anticancer therapeutics Mol. Cancer Ther., April 1, 2005; 4(4): 677 - 685. [Abstract] [Full Text] [PDF]

				M. F. McCarty Targeting Multiple Signaling Pathways as a Strategy for Managing Prostate Cancer: Multifocal Signal Modulation Therapy Integr Cancer Ther, December 1, 2004; 3(4): 349 - 380. [Abstract] [PDF]

				B. Zhang, Y. Zhang, and E. Shacter Rac1 Inhibits Apoptosis in Human Lymphoma Cells by Stimulating Bad Phosphorylation on Ser-75 Mol. Cell. Biol., July 15, 2004; 24(14): 6205 - 6214. [Abstract] [Full Text] [PDF]