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Hot Topic Event - Pseudokinases as modulators of signal transduction in normal and cancer cells

3 December 2010

Charles Darwin House, London, UK



Meeting background

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 signalling 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 signalling 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.

 

References


 

Organizers:
James Murphy (Walter and Eliza Hall Institute of Medical Research, Australia)
Dario Alessi (University of Dundee, UK)

Session 1: Pseudokinase classification and technical challenges

 

Chair:
James Murphy (Walter and Eliza Hall Institute of Medical Research, Australia)
Friday 3 December 2010
08:30 - 09:50 Registration with tea and coffee

09:50 - 10:00
Welcome and introduction by James Murphy (Walter and Eliza Hall Institute of Medical Research, Australia)
10:00 - 10:35
Genomics and evolution of pseudokinases
Gerard Manning (Salk Institute, USA)
10:35 - 11:00
Pseudokinase TRB2 exhibits Mg2+-sensitive kinase activity in vitro
Selected oral communication - Patrick Eyers (University of Sheffield, UK)
11:00 - 11:30 Coffee/tea break

Session 2: Biochemistry and structural biology

 

Chair:
Jane Endicott (University of Oxford, UK)
Friday 3 December 2010
11:30 - 12:05
Structure of ILK pseudokinase: a new look of the ILK function in cytoskeleton and cell adhesion
Jun Qin (Lerner Research Institute, USA)
12:05 - 12:40
Structure and function of the STRAD pseudokinase
Dario Alessi (University of Dundee, UK)
12:40 - 13:05
The crystal structure of a MEK-KSR complex reveals a mechanism of KSR-mediated regulation of MEK phosphorylation by RAF
Selected oral communication - David Barford (Institute of Cancer Research, UK)
13:00 - 13:30
Allosteric function of the inactive HER3 receptor
Selected oral communication - Natalia Jura (University of California, San Francisco, USA)
13:30 - 14:30 Lunch and informal discussions

Session 3: Pseudokinases in normal and cancer cells - Part I

 

Chair:
Endre Kiss-Toth (University of Sheffield, UK)
Friday 3 December 2010
14:30 - 15:05
Characterization of the pseudokinase domain in JAK2
Olli Silvennoinen (University of Tampere, Finland)
15:05 - 15:30
Molecular pathogenesis of human myeloproliferative neoplasms
Selected oral communication - Tony Green (University of Cambridge, UK)
15:30 - 15:55
Pseudokinase domain helix C is pivotal for constitutive activation of JAK2 V617F and other JAK mutants but not for cytokine-dependent JAK activation
Selected oral communication - Stefan Constantinescu (Catholic University of Leuven, Belgium)
15:55 - 16:20 Coffee and tea break

Session 4: Pseudokinases in normal and cancer cells – Part II

 

Chair:
Dario Alessi (University of Dundee, UK)
Friday 3 December 2010
16:20 - 16:45
Inhibition of JAK-STAT signalling by SOCS3
Selected oral communication - Warren Alexander (Walter and Eliza Hall Institute of Medical Research, Australia)
16:45 - 17:10
Structural and functional regulation of Trib family of pseudokinases in normal and AML cells
Selected oral communication - Karen Keeshan (University College Cork, RoI)
17:10 - 17:35
Evolution and mitotic function of the putative pseudokinase BUBR1
Selected oral communication - Geert Kops (Utrecht University, The Netherlands)
17:35 - 18:10
Insight into pseudo-kinase evolution provided by the structural characterization of PKR, Ire1 and Raf protein kinases
Frank Sicheri (Samuel Lunenfeld Research Institute, Canada)
18:10 - 18:15
Concluding remarks by Dario Alessi (University of Dundee, UK)
18:15 - 19:30 Poster session and drinks reception

20:00 - 22:00 Conference dinner