Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

Common Docking Domain Mutation E322K of the ERK2 Gene is Infrequent in Oral Squamous Cell Carcinomas

  • Valiathan, Gopalakrishnan Mohan (Department of Periodontia, Sree Balaji Medical and Dental College and Hospital, Bharath University) ;
  • Thenumgal, Siji Jacob (Department of Periodontia, Rajah Muthiah Dental College and Hospital, Annamalai University) ;
  • Jayaraman, Bhaskar (Department of Periodontia, Sree Balaji Medical and Dental College and Hospital, Bharath University) ;
  • Palaniyandi, Arunmozhi (Department of Periodontia, Rajah Muthiah Dental College and Hospital, Annamalai University) ;
  • Ramkumar, Hemalatha (Department of Pedodontia, S.R.M Dental College and Hospital, S.R.M University) ;
  • Jayakumar, Keerthivasan (Human Genetics Laboratory, Sree Balaji Medical and Dental College and Hospital, Bharath University) ;
  • Bhaskaran, Sajeev (Department of Conservative Dentistry, Vananchal Dental College and Hospital) ;
  • Ramanathan, Arvind (Human Genetics Laboratory, Sree Balaji Medical and Dental College and Hospital, Bharath University)
  • Published : 2012.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Mutations in the MAPK (Mitogen Activated Protein Kinase) signaling pathway - EGFR/Ras/RAF/MEK have been associated with the development of several carcinomas. ERK2, a downstream target of the MAPK pathway and a founding member of the MAPK family is activated by cellular signals emanating at the cell membrane. Activated ERK2 translocates into the nucleus to transactivate genes that promote cell proliferation. MKP - a dual specific phosphatase - interacts with activated ERK2 via the common docking (CD) domain of the later to inactivate (dephosphorylate) and effectively terminate further cell proliferation. A constitutively active form of ERK2 carrying a single point mutation - E322K in its CD domain, was earlier reported by our laboratory. In the present study, we investigated the prevalence of this CD domain E322K mutation in 88 well differentiated OSCC tissue samples. Materials and Method: Genomic DNA specimens isolated from 88 oral squamous cell carcinoma tissue samples were amplified with primers flanking the CD domain of the ERK2 gene. Subsequently, PCR amplicons were gel purified and subjected to direct sequencing to screen for mutations. Results: Direct sequencing of eighty eight OSCC samples identified an E322K CD domain mutation in only one (1.1%) OSCC sample. Conclusions: Our result indicates that mutation in the CD domain of ERK2 is rare in OSCC patients, which suggests the role of genetic alterations in other mitogenic genes in the development of carcinoma in the rest of the patients. Nevertheless, the finding is clinically significant, as the relatively rare prevalence of the E322K mutation in OSCC suggests that ERK2, being a common end point signal in the multi-hierarchical mitogen activated signaling pathway may be explored as a viable drug target in the treatment of OSCC.

Keywords

References

  1. Arvind R, Shimamoto H, Momose F, et al (2005). A mutation in the common docking domain of ERK2 in a human cancer cell line, which was associated with its constitutive phosphorylation. Int J Oncol, 27, 1499-504.
  2. Chappell WH, Steelman LS, Long JM, et al (2011). Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget, 2, 135-64.
  3. Chu Y, Solski PA, Khosravi-Far R, Der CJ, Kelly K (1996). The mitogen-activated protein kinase phosphatases PAC1, MKP-1, and MKP-2 have unique substrate specificities and reduced activity in vivo toward the ERK2 sevenmaker mutation. J Biol Chem, 271, 6497-501. https://doi.org/10.1074/jbc.271.11.6497
  4. Falchook GS, Lewis KD, Infante JR, et al (2012). Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol, 13, 782-9. https://doi.org/10.1016/S1470-2045(12)70269-3
  5. Friday BB, Adjei AA (2008). Advances in targeting the Ras/Raf/MEK/Erk mitogen-activated protein kinase cascade with MEK inhibitors for cancer therapy. Clin Cancer Res, 14, 342-6. https://doi.org/10.1158/1078-0432.CCR-07-4790
  6. Gaestel M (2008). Specificity of signaling from MAPKs to MAPKAPKs: kinases' tango Nuevo. Front Biosci, 13, 6050-9.
  7. Greulich H, Chen T-H, Feng W, et al (2005). Oncogenic Transformation by Inhibitor-Sensitive and -Resistant EGFR Mutants. PLoS Med, 2, 313. https://doi.org/10.1371/journal.pmed.0020313
  8. Hsieh CH, Chang JW, Hsieh JJ (2011). Epidermal growth factor receptor mutations in patients with oral cavity cancer in a betel nut chewing-prevalent area. Head Neck, 33, 1758-64. https://doi.org/10.1002/hed.21665
  9. Keyse SM (2008). Dual-specificity MAP kinase phosphatases (MKPs) and cancer. Cancer Metastasis Rev, 27, 253-61. https://doi.org/10.1007/s10555-008-9123-1
  10. Laimer K, Spizzo G, Gastl G, et al (2007). High EGFR expression predicts poor prognosis in patients with squamous cell carcinoma of the oral cavity and oropharynx: a TMAbased immunohistochemical analysis. Oral Oncol, 43, 193-8. https://doi.org/10.1016/j.oraloncology.2006.02.009
  11. Mahalingam M, Arvind R, Ida H, et al (2008). ERK2 CD domain mutation from a human cancer cell line enhanced anchorageindependent cell growth and abnormality in Drosophila. Oncol Rep, 20, 957-62.
  12. McCubrey JA, Steelman LS, Chappell WH, et al (2007). Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta, 1773, 1263-84. https://doi.org/10.1016/j.bbamcr.2006.10.001
  13. Mitra RS, Zhang Z, Henson BS, et al (2003). Rap1A and rap1B ras-family proteins are prominently expressed in the nucleus of squamous carcinomas: nuclear translocation of GTPbound active form. Oncogene, 22, 6243-56. https://doi.org/10.1038/sj.onc.1206534
  14. Montagut C, Settleman J (2009). Targeting the RAF-MEK-ERK pathway in cancer therapy. Cancer Lett, 283, 125-34. https://doi.org/10.1016/j.canlet.2009.01.022
  15. Murugan AK, Munirajan AK, Tsuchida N (2012). Ras oncogenes in oral cancer: the past 20 years. Oral Oncol, 48, 383-92. https://doi.org/10.1016/j.oraloncology.2011.12.006
  16. Plyte S, Majolini MB, Pacini S, et al (2000). Constitutive activation of the Ras/MAP kinase pathway and enhanced TCR signaling by targeting the Shc adaptor to membrane rafts. Oncogene, 19, 1529-37. https://doi.org/10.1038/sj.onc.1203451
  17. Roberts PJ, Der CJ (2007). Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene, 26, 3291-310. https://doi.org/10.1038/sj.onc.1210422
  18. Schreck R, Rapp UR (2006). Raf kinases: oncogenesis and drug discovery. Int J Cancer, 119, 2261-71. https://doi.org/10.1002/ijc.22144
  19. Severino P, Alvares AM, Michaluart P Jr (2008). Global gene expression profiling of oral cavity cancers suggests molecular heterogeneity within anatomic subsites. BMC Res Notes, 1, 113. https://doi.org/10.1186/1756-0500-1-113
  20. Steelman LS, Franklin RA, Abrams SL, et al (2011). Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy. Leukemia, 25, 1080-94. https://doi.org/10.1038/leu.2011.66
  21. Szabo B, Nelhubel GA, Karpati A, et al (2011). Clinical significance of genetic alterations and expression of epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinomas. Oral Oncol, 47, 487-96. https://doi.org/10.1016/j.oraloncology.2011.03.020
  22. Tanoue T, Adachi M, Moriguchi T, Nishida E (2000). A conserved docking motif in MAP kinases common to substrates, activators and regulators. Nat Cell Biol, 2, 110-6. https://doi.org/10.1038/35000065
  23. Van Damme N, Deron P, Van Roy N (2010). Epidermal growth factor receptor and K-RAS status in two cohorts of squamous cell carcinomas. BMC Cancer, 11, 189.
  24. Wang YS, Wang YH, Xia HP, et al (2012). MicroRNA-214 regulates the acquired resistance to gefitinib via the PTEN/AKT pathway in EGFR-mutant cell lines. Asian Pac J Cancer Prev, 13, 255-60. https://doi.org/10.7314/APJCP.2012.13.1.255
  25. Yoon S, Seger R (2006). The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors, 24, 21-44. https://doi.org/10.1080/02699050500284218

Cited by

  1. A Novel Heterozygous Mutation (F252Y) in Exon 7 of the IRF6 Gene is Associated with Oral Squamous Cell Carcinomas vol.14, pp.11, 2013, https://doi.org/10.7314/APJCP.2013.14.11.6803
  2. Tyrosine 1045 Codon Mutations in Exon 27 of EGFR are Infrequent in Oral Squamous Cell Carcinomas vol.14, pp.7, 2013, https://doi.org/10.7314/APJCP.2013.14.7.4279