Bivalent JNK inhibitor

A Small Molecule Bidentate-Binding Dual Inhibitor Probe of the LRRK2 and JNK Kinases

ACS Chem. Biol., Article ASAP

http://pubs.acs.org/doi/abs/10.1021/cb3006165

I'm a big fan of the LoGrasso group's work on JNKs. Here they used a bivalent approach to target both the adenosine pocket and the substrate-binding pocket.

EGFR dynamics

Effects of oncogenic mutations on the conformational free-energy landscape of EGFR kinase

PNAS June 10, 2013
http://www.pnas.org/content/early/2013/06/07/1221953110.short

I can't say I'm a fan of purely computational work without a healthy dose of experimental evidence, but this is nonetheless a nice paper on the dynamics of EGFR.

Fam20C is the Golgi casein kinase

Crystal structure of the Golgi casein kinase

PNAS June 10, 2013

http://www.pnas.org/content/early/2013/06/06/1309211110.short

I saw Jack Dixon present this work at this year's ASBMB. It was a great story, so I was looking forward to this paper. 

Erk gets help from Elk to bind DNA

Genome-wide Kinase-Chromatin Interactions Reveal the Regulatory Network of ERK Signaling in Human Embryonic Stem Cells

Molecular Cell, Available online 30 May 2013

http://www.sciencedirect.com/science/article/pii/S1097276513003353

This paper reports that Elk works in concert with Erk to bind DNA. I wonder what Erk is doing near noncoding regions.

EGFR tail

Target Binding Properties and Cellular Activity of Afatinib (BIBW 2992), an Irreversible ErbB Family Blocker

J Pharmacol Exp Ther. 2012 Nov;343(2):342-50

http://jpet.aspetjournals.org/content/343/2/342.long

Normally I would discuss this paper, but it appears that there is a whole other paper devoted to it and the crystal structure it reports:

EGFR: Tale of the C-terminal tail
Protein Sci. 2013 May 15
http://onlinelibrary.wiley.com/doi/10.1002/pro.2283/abstract

The RAF saga continues

RAF Inhibitors Activate the MAPK Pathway by Relieving Inhibitory Autophosphorylation

Cancer Cell, Volume 23, Issue 5, 594-602, 13 May 2013

http://www.sciencedirect.com/science/article/pii/S1535610813001347

(Also comment at http://www.sciencedirect.com/science/article/pii/S1535610813001347)

People in this field have been trying to figure out why RAF drugs induce the Erk MAPK pathway. This paper reports a new mechanism for RAF regulation and MAPK activation. Normally p-loop autphosphorylation (in trans as a dimer) of RAF inhibits the kinase. By adding low amounts of the inhibitors they developed, one of the monomers remains unphosphorylated and can activate the MEK-ERK pathway. But if they add even more inhibitor, both monomers are inhibited. Pretty neat.

p38-mediated senescence

A Posttranslational Modification Cascade Involving p38, Tip60, and PRAK Mediates Oncogene-Induced Senescence

Molecular Cell, 16 May 2013

http://www.sciencedirect.com/science/article/pii/S1097276513002943

I'm glad the authors defined the word "senescence" in the first sentence. I had also never heard of PRAK or Tip60, so I was off to a pretty bad start with this paper. Fortunately it was pretty straightforward: they used yeast-two-hybrid to find that Tip60 interacts with the kinase PRAK. Then they did a ton of experiments (manifested by an even greater number of western blots) to show that ras-activated p38 phosphorylates both PRAK and Tip60, which also acetylates PRAK. These modifications activate PRAK, which has pro-senescent properties.