Pseudokinases as modulators of signal transduction in normal and cancer cells 2010

Pseudokinases are a protein family that constitute ~10% of the human kinome, characterized by the presence of a kinase-homology domain predicted to lack phosphoryl-transfer catalytic activity due to the absence of critical catalytic motifs.

Owing to their lack of intrinsic phosphoryl-transfer catalytic activity, pseudokinase domain-containing proteins have long thought to be bystanders in intracellular signaling pathways rather than active participants. However, recent studies have provided overwhelming evidence in support of the view that pseudokinase domain-containing proteins play crucial roles in signal transduction, principally via the regulation of catalytically-active bona fide kinases (Saharinen et al., 2000; Boudeau et al., 2006; Zeqiraj et al., 2009; Rajakulendran et al., 2009).

Of critical importance, mutations affecting pseudokinase domains underlie the dysregulation of catalytic activity of several clinically-important kinases, including LKB1, Raf and Jak2, by their partner pseudokinase regulators, STRAD, KSR and the Jak2 JH2 domain, respectively (Boudeau et al., 2003; Rajakulendran et al., 2009; James et al., 2005; Baxter et al., 2005). These studies have provided a direct link between pseudokinase-mediated dysregulation of signal transduction and a number of devastating human diseases, including cancers and blood cell malignancies.

The molecular details underlying pseudokinase modulation of signal transduction in normal and cancer cells have only recently begun to emerge with a surge in structure-function studies over the past two years (e.g. Scheeff et al., 2009; Zeqiraj et al., 2009). However, to date, few of the 48 predicted human pseudokinase domains have been functionally or structurally characterized, and consequently their roles in cell signaling remain to be discovered.

This Hot Topic in Biochemistry Event will comprise one day of oral presentations and a poster session. The program will focus on pseudokinase classification and evolution, the molecular mechanisms by which pseudokinases regulate signal transduction, and how mutations affecting pseudokinases can cause human disease. Oral presentations will be selected from submitted abstracts to complement a program of distinguished invited speakers.