Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mirk/Dyrk1B is a member of a conserved family of serine/threonine kinases which are activated by intramolecular tyrosine phosphorylation, and which mediate differentiation in different tissues-Mirk in skeletal muscle, Dyrk1A in the brain, etc. One role of Mirk in skeletal muscle differentiation is to block cycling myoblasts in the G0 quiescent state by modification of cell cycle regulators, while another role of Mirk is to limit apoptosis in fusing myoblasts. Amplification of the Mirk gene, upregulation of Mirk expression and/or constitutive activation of this kinase have been observed in several different types of cancer. If coupled with a stress condition such as serum starvation which induces a quiescent state, depletion of Mirk by RNA interference using either synthetic duplex RNAi's or pSilencer-encoded RNAi's have decreased colony formation of different cancer cell lines and enhanced apoptosis induced by chemotherapeutic drugs. Mirk is activated by phosphorylation by the stress-activated SAPK kinases MKK3 and MKK6. Our working hypothesis is that Mirk is activated by this pathway in response to various stresses, and then acts as a checkpoint kinase to arrest damaged tumor cells in a quiescent state and allow cellular repair. Pharmacological inhibition of Mirk may enhance the anti-tumor effect of chemotherapeutic drugs.
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PMID:Mirk/Dyrk1B in cancer. 1758 56

The dual-specificity tyrosine-phosphorylation-regulated kinase, DYRK1B, is expressed de novo during myogenesis, amplified or mutated in certain cancers and mutated in familial cases of metabolic syndrome. DYRK1B is activated by cis auto-phosphorylation on tyrosine-273 (Y273) within the activation loop during translation but few other DYRK1B phosphorylation sites have been characterised to date. Here, we demonstrate that DYRK1B also undergoes trans-autophosphorylation on serine-421 (S421) in vitro and in cells and that this site contributes to DYRK1B kinase activity. Whilst a DYRK1B(S421A) mutant was completely defective for p-S421 in cells, DYRK1B inhibitors caused only a partial loss of p-S421 suggesting the existence of an additional kinase that could also phosphorylate DYRK1B S421. Indeed, a catalytically inactive DYRK1B(D239A) mutant exhibited very low levels of p-S421 in cells but this was increased by KRAS(G12V). In addition, selective activation of the RAF-MEK1/2-ERK1/2 signalling pathway rapidly increased p-S421 in cells whereas activation of the stress kinases JNK or p38 could not. S421 resides within a Ser-Pro phosphoacceptor motif that is typical for ERK1/2 and recombinant ERK2 phosphorylated DYRK1B at S421 in vitro. Our results show that DYRK1B is a novel ERK2 substrate, uncovering new links between two kinases involved in cell fate decisions. Finally, we show that DYRK1B mutants that have recently been described in cancer and metabolic syndrome exhibit normal or reduced intrinsic kinase activity.
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PMID:Identification of DYRK1B as a substrate of ERK1/2 and characterisation of the kinase activity of DYRK1B mutants from cancer and metabolic syndrome. 2634 93