Elton Zeqiraj awarded the 2009 Howard Elder Prize for Cancer Research
Elton Zeqiraj an MRC Unit PhD student jointly supervised by Dario Alessi and Daan van Aalten has been awarded the 2009 Howard Elder Prize for Cancer Research for his spectacular PhD research that has lead to the resolution of the three dimensional structure of the LKB1:STRADa:MO25a. To read Elton's award-winning paper click here.
Elton's PhD research project was generously supported by TENOVUS Scotland. The committee selecting Elton for this award was composed of Ninewells-based researchers Paul Clarke, Steve Keyse and John Hayes. They commented that 'Elton's work is not only a superb and important piece of work with clear relevance to cancer, but we also selected Elton because he clearly contributed a great deal to the success of the project.'
Much research in the MRC Protein Phosphorylation Unit over the last 11 years has focused on understanding the LKB1 tumour suppressor protein kinase that is frequently mutated in many human cancers. It is now clear that LKB1 exerts its cancer suppressing effects by activating a group of other ~14 kinases comprising AMPK and AMPK-related kinases. Activation of AMPK by LKB1 suppresses cell growth under conditions of low cell energy Activation of AMPK-related kinases by LKB1 appears to regulate cell polarity and contribute to inhibiting inappropriate expansion of tumour cells.
A fascinating feature of LKB1 is that it is activated by an unusual allosteric mechanism involving interaction with an inactive pseudokinase termed STRAD and a scaffolding protein termed MO25. Prior to Elton's work how STRAD and MO25 cooperate to activate LKB1 was not known. For his PhD project Elton courageously took up the challenge to crystallize the complete LKB1:STRAD:MO25 heterotrimeric complex. This was an extremely challenging project. Elton worked tirelessly for over 3 years attempting to express many constructs in both bacterial and insect cell systems to generate sufficient complex to permit crystallographic analysis. This effort paid off at the beginning of the 4th year of his PhD project when he succeeded in crystallising and solving the structure of the complete heterotrimeric LKB1:STRAD:MO25 complex expressed in insect cells using a baculovius expression system. A stunning movie of the crystal structure of the heterotrimeric LKB1 crystal structure can be viewed in YouTube.
With lots of help from Beatrice Filippi, Elton analysed the effect that over 100 mutations in interesting regions of the LKB1 complex had on complex assembly and activity. These data provide a remarkable molecular insight of how LKB1 is activated by binding to STRAD and MO25. The pseudokinase STRAD subunit despite being catalytically inactive binds ATP and adopts a closed conformation typical of active protein kinases. LKB1 interacts with STRAD as a pseudosubstrate. LKB1 is maintained in an active conformation by forming a web of interactions with both STRAD and MO25.
The finding that STRAD despite being catalytically inactive, exerts its biological function by folding into an active conformation and binding LKB1 in the same manner as an active kinase would interact with a substrate, is likely to be relevant to understanding the evolution and function of other poorly studied pseudokinases (of which there are ~40 encoded by the human genome). It also suggests that active protein kinases could exert physiological responses by binding to substrates without necessarily needing to phosphorylate them. Finally, another very important aspect of Elton's study is that the structure of the LKB1 complex also reveals how ~60 different LKB1 mutations found in diverse human cancers impair LKB1 function.
The Howard Elder Prize was endowed by Dr Alison Burt in memory of her father (Dr Howard Elder, a former medical graduate of the University of Dundee) 25 years ago. The prize is awarded to a PhD student or postdoctoral researcher in the College of Life Sciences deemed to have published the most significant paper in an area related to cancer research. Elton is now undertaking Postdoctoral Research in Frank Sicheri's laboratory at the Samuel Lunenfeld Research institute, Toronto Canada. He hopes to return to Dundee to collect his award in April 2010.
This is the second year in a row that the Howard Elder Prize has been awarded to an MRC Unit researcher working in the Alessi lab as last years prize went to Xu Huang for his work in defining the importance of the LKB1 pathway in modulating tumourigenesis.
Elton's PhD research project was generously supported by TENOVUS Scotland. The committee selecting Elton for this award was composed of Ninewells-based researchers Paul Clarke, Steve Keyse and John Hayes. They commented that 'Elton's work is not only a superb and important piece of work with clear relevance to cancer, but we also selected Elton because he clearly contributed a great deal to the success of the project.'
Much research in the MRC Protein Phosphorylation Unit over the last 11 years has focused on understanding the LKB1 tumour suppressor protein kinase that is frequently mutated in many human cancers. It is now clear that LKB1 exerts its cancer suppressing effects by activating a group of other ~14 kinases comprising AMPK and AMPK-related kinases. Activation of AMPK by LKB1 suppresses cell growth under conditions of low cell energy Activation of AMPK-related kinases by LKB1 appears to regulate cell polarity and contribute to inhibiting inappropriate expansion of tumour cells.
A fascinating feature of LKB1 is that it is activated by an unusual allosteric mechanism involving interaction with an inactive pseudokinase termed STRAD and a scaffolding protein termed MO25. Prior to Elton's work how STRAD and MO25 cooperate to activate LKB1 was not known. For his PhD project Elton courageously took up the challenge to crystallize the complete LKB1:STRAD:MO25 heterotrimeric complex. This was an extremely challenging project. Elton worked tirelessly for over 3 years attempting to express many constructs in both bacterial and insect cell systems to generate sufficient complex to permit crystallographic analysis. This effort paid off at the beginning of the 4th year of his PhD project when he succeeded in crystallising and solving the structure of the complete heterotrimeric LKB1:STRAD:MO25 complex expressed in insect cells using a baculovius expression system. A stunning movie of the crystal structure of the heterotrimeric LKB1 crystal structure can be viewed in YouTube.
With lots of help from Beatrice Filippi, Elton analysed the effect that over 100 mutations in interesting regions of the LKB1 complex had on complex assembly and activity. These data provide a remarkable molecular insight of how LKB1 is activated by binding to STRAD and MO25. The pseudokinase STRAD subunit despite being catalytically inactive binds ATP and adopts a closed conformation typical of active protein kinases. LKB1 interacts with STRAD as a pseudosubstrate. LKB1 is maintained in an active conformation by forming a web of interactions with both STRAD and MO25.
The finding that STRAD despite being catalytically inactive, exerts its biological function by folding into an active conformation and binding LKB1 in the same manner as an active kinase would interact with a substrate, is likely to be relevant to understanding the evolution and function of other poorly studied pseudokinases (of which there are ~40 encoded by the human genome). It also suggests that active protein kinases could exert physiological responses by binding to substrates without necessarily needing to phosphorylate them. Finally, another very important aspect of Elton's study is that the structure of the LKB1 complex also reveals how ~60 different LKB1 mutations found in diverse human cancers impair LKB1 function.
The Howard Elder Prize was endowed by Dr Alison Burt in memory of her father (Dr Howard Elder, a former medical graduate of the University of Dundee) 25 years ago. The prize is awarded to a PhD student or postdoctoral researcher in the College of Life Sciences deemed to have published the most significant paper in an area related to cancer research. Elton is now undertaking Postdoctoral Research in Frank Sicheri's laboratory at the Samuel Lunenfeld Research institute, Toronto Canada. He hopes to return to Dundee to collect his award in April 2010.
This is the second year in a row that the Howard Elder Prize has been awarded to an MRC Unit researcher working in the Alessi lab as last years prize went to Xu Huang for his work in defining the importance of the LKB1 pathway in modulating tumourigenesis.