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Review
. 2012 Jul;11(4):300-10.
doi: 10.1093/bfgp/els022. Epub 2012 Jun 29.

MEK genomics in development and disease

Jennifer L Bromberg-White  1 , Nicholas J Andersen, Nicholas S Duesbery
Affiliations
Review

MEK genomics in development and disease

Jennifer L Bromberg-White et al. Brief Funct Genomics. 2012 Jul.

Abstract

The mitogen-activated protein kinase kinases (the MAPK/ERK kinases; MKKs or MEKs) and their downstream substrates, the extracellular-regulated kinases have been intensively studied for their roles in development and disease. Until recently, it had been assumed any mutation affecting their function would have lethal consequences. However, the identification of MEK1 and MEK2 mutations in developmental syndromes as well as chemotherapy-resistant tumors, and the discovery of genomic variants in MEK1 and MEK2 have led to the realization the extent of genomic variation associated with MEKs is much greater than had been appreciated. In this review, we will discuss these recent advances, relating them to what is currently understood about the structure and function of MEKs, and describe how they change our understanding of the role of MEKs in development and disease.

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Figures

Figure 1:
Figure 1:
A linear model of MEK 1 and MEK 2 showing locations of identified functional regions and mutations. Linear models of MEK 1 and MEK 2 are used to indicate the locations of functional domains in both kinases. Above each is a scale with hash marks at the locations of predicted phosphorylation sites (red), experimentally identified phosphorylation sites (red hash with oval), syndrome-associated mutations (purple), somatic cancer mutations (green), and SNPs (blue). Numbers indicate amino acid position starting from the first Met residue.
Figure 2:
Figure 2:
A 3D model of MEK 1 showing a mutational hot spot. A 3D X-ray model of residues 35–382 of MEK 1 in a binary complex with ADP and Mg2+ [29] rendered in worms with Cn3D software was used to map the locations of syndromic and cancer-related mutations as well as germline variants. The model is oriented with the small amino-terminal catalytic lobe colored pink at the top and the large catalytic lobe in blue at the bottom. ADP and Mg2+ are shown in the cleft between the two lobes. The amino terminus is represented on the left in grey. Mutated residues are indicated in yellow.
See this image and copyright information in PMC

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