All tags Cancer ERK1/2-signaling in cancer

ERK1/2-signaling in cancer

by Seán Mac Fhearraigh, PhD

The Ras-Raf-MEK-ERK/MAPK pathway is highly conserved in metazoans and controls many of the principal pathways involved in cell motility, metabolism, cell proliferation, differentiation and apoptosis [Kolch, 2005].

Initiation of the Ras-Raf- MEK/MAPK pathway can occur through receptor tyrosine kinase (RTK) activation. RTKs act as entry points for many extracellular cues as they contain an N-terminal extracellular ligand binding domain and C-terminal intracellular tyrosine kinase domain [McKay and Morrison, 2007; Pawson, 2002].

Upon binding of their respective ligands, RTKs undergo dimerisation and autophosphorylation of tyrosine residues within their C-terminal intracellular domain.

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Activation of RasGTPase is a key step allowing for signal transduction from RTKs to ERK1/2 MAPK. RasGTPases are a superfamily of small monomeric GTPases which include NRAS, KRAS and HRAS [Downward, 2003].

One of the most intensively studied activators of Ras is the SOS (Son of sevenless homologue 1) guanine nucleotide exchange factor (GEF) [Downward, 1996]. GRB2 mediates the translocation of SOS from the cytosol to the plasma membrane upon RTK activation, resulting in the activation of Ras through GTP exchange.

Activated Ras then binds to and recruits the Raf kinase to the cell membrane. The RAF gene produces three isoforms (A-Raf, B-Raf and Raf-1), and each isoform has specific functions.

The Raf kinase is the apical kinase in a three-tier phosphorylation activation cascade, where Raf phosphorylates and activates MEK1 and MEK2, which in turn phosphorylates activates and ERK1/2 [Vigil et al., 2010]. Once activated ERK1/2 phosphorylates a spectrum of substrates in both the cytosol and nucleus which include phosphatases, kinases, cytoskeletal proteins and transcription factors which play an integral role in cell death and cell proliferation [Yoon and Seger, 2006].

Deregulation of the ERK pathway

Deregulation of the ERK pathway occurs in up to one-third of all cancers. Due to its anti-apoptotic and proliferative affects, ERK1/2 is a central player in the propagation of many forms of cancer.

ERK becomes constitutively active following aberrant expression of tyrosine kinases and following sustained paracrine or autocrine signalling, and B-Raf or Ras mutations [Dhillon et al., 2007].

For example, malignant melanoma is a highly aggressive cancer that is resistant to chemotherapy [Houghton and Polsky, 2002]. Approximately 60% of melanomas contain somatic B-Raf missense mutations which are found within the kinase domain of B-Raf.

The V600E missense mutation accounts for 80% of all mutations [Davies et al., 2002]. The B-RafV600E mutant results in a dramatic elevation in its kinase activity leading to increased ERK1/2 kinase activity in vivo [Wan et al., 2004].

References

  • Davies, H., G. R. Bignell, et al. (2002). "Mutations of the BRAF gene in human cancer." Nature 417(6892): 949-54.
  • Dhillon, A. S., S. Hagan, et al. (2007). "MAP kinase signalling pathways in cancer." Oncogene 26(22): 3279-90.
  • Downward, J. (1996). "Control of ras activation." Cancer Surv 27: 87-100.
  • Downward, J. (2003). "Targeting RAS signalling pathways in cancer therapy." Nat Rev Cancer 3(1): 11-22.
  • Houghton, A. N. and D. Polsky (2002). "Focus on melanoma." Cancer Cell 2(4): 275-8.
  • Kolch, W. (2005). "Coordinating ERK/MAPK signalling through scaffolds and inhibitors." Nat Rev Mol Cell Biol 6(11): 827-37.
  • McKay, M. M. and D. K. Morrison (2007). "Integrating signals from RTKs to ERK/MAPK." Oncogene 26(22): 3113-21.
  • Pawson, T. (2002). "Regulation and targets of receptor tyrosine kinases." Eur J Cancer 38 Suppl 5: S3-10.
  • Yoon, S. and R. Seger (2006). "The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions." Growth Factors 24(1): 21-44.
  • Vigil, D., J. Cherfils, et al. "Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?" Nat Rev Cancer 10(12): 842-57.
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