December 2013

Keeping up with kinases

kinase figure
Click on the image to see a fuller-sized version of this figure.

Without protein kinases, we wouldn’t have much signal transduction in cells. But identifying the relationship between these critical molecular machines and their numerous substrates has been a challenge. In a paper in a recent issue of Molecular & Cellular Proteomics, a team led by W. Andy Tao at Purdue University described a proteomic approach to identify directly the substrates of tyrosine kinases.
 
Tao’s group’s approach involved two steps. In the first step, the investigators did an in vitro screen to look for substrates phosphorylated by a particular kinase. In the second step, with an in vivo assay, they looked for which substrates were phosphorylated when human lymphoma cells were treated with an inhibitor against the same kinase. By comparing and contrasting the two datasets, Tao and colleagues were able to identify many of the substrates for a given kinase. (As proof of principle, the investigators studied the kinase SYK.) Their approach identified many more substrates than the traditional molecular-biology approaches, which can identify only one substrate at a time.
 
The work has potential clinical implications. “Many kinases, in particular tyrosine kinases, have been discovered as oncogenes in a number of cancer types,” explains Tao. “While they are targeted to develop inhibitors as drug candidates, their network, in particular the precise relationship between kinases and their substrates, is not clear in most cases. The lack of specific knowledge has hindered us from developing better and more potent drugs and from addressing the difficult issue of drug resistance in chemotherapy.”
 
The investigators intend to extend their strategy to serine/threonine kinases and look at diseases caused by mutated kinase-substrate interactions.

Rajendrani MukhopadhyayRajendrani Mukhopadhyay (rmukhopadhyay@asbmb.org) is the senior science writer and blogger for ASBMB. Follow her on Twitter (www.twitter.com/rajmukhop), and read her ASBMB Today blog, Wild Types.


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