• University of Tasmania Featured PhD Programmes
  • Aberdeen University Featured PhD Programmes
  • University of Pennsylvania Featured PhD Programmes
  • Staffordshire University Featured PhD Programmes
  • University of Cambridge Featured PhD Programmes
University of York Featured PhD Programmes
Peter MacCallum Cancer Centre Featured PhD Programmes
University of Leeds Featured PhD Programmes
University of Liverpool Featured PhD Programmes
University of Reading Featured PhD Programmes

G proteins and their effectors as therapeutic targets in invasion and metastasis

  • Full or part time
    Dr Darerca Owen
  • Application Deadline
    Applications accepted all year round
  • Awaiting Funding Decision/Possible External Funding
    Awaiting Funding Decision/Possible External Funding

Project Description

For the majority of cancers the acquisition of invasive and metastatic characteristics leads to incurable disease in the host. A major challenge, therefore, is the elucidation of the underlying molecular changes that lead to the unimpeded ability of tumour cells to invade neighbouring tissue and disperse to secondary sites and the development of therapies to arrest such a progression. Small G proteins, particularly members of the Rho family, are known regulators of the actin cytoskeleton and therefore control the morphology and motility of mammalian cells. It is not surprising therefore, that they are implicated with increasing frequency in the transition to invasive and metastatic forms of cancers. This implies the existence of a therapeutic avenue directed against these proteins and their downstream effectors.

Our work addresses the relationship between structure and function in small G proteins and their effector complexes. We have determined several structures (by NMR) of small G proteins (primarily of the Rho family) in complex with the G protein binding domains of their effector proteins. Our structures facilitated the design of mutations that selectively inhibited the interaction of Cdc42 with its effectors. Thermodynamic analysis of these mutants led to the identification of ’hotspots’ on the G protein surface that define areas which could be targeted by small molecules for therapeutic purposes. We are now using this information to generate lead therapeutic molecules. We also have a major programme of work currently underway to delineate the role of the Cdc42 effector, ACK, in tumourigenesis.

Recently, we have also extended our investigations to include the Ras family members, Ral A and B. A major focus of our recent efforts has been to forge a comprehensive programme of work to target the Ral proteins and their effector, RLIP76 for therapeutic purposes. These proteins are critical moderators of cancer progression and there is an urgent need for targetted therapies against them. This work involves the development of lead therapeutic but also concentrates on defining the role of the Ral/RLIP76 signalling axis in carcinogenesis.

Funding Notes

Applicants should hold or be about to achieve a First or Upper-Second (2.i) class degree in a relevant subject. RC-UK studentships are available to UK nationals and EU students who meet the UK residency requirements. Further information about eligibility for Research Council UK funding can be found on the BBSRC/MRC websites e.g. : View Website

Applicants with full funding from a competitive source will also be considered

References

Rittinger, K. et al.(1997) Crystal Structure of a small G protein in complex with the GTPase-activating protein RhoGAP. Nature 388:693

Mott, H.R., et al.(1999) Structure of the small G protein Cdc42 bound to the GTPase-binding domain of ACK Tyrosine Kinase. Nature 399:384.

Morreale, A. et al.(2000) Structure of Cdc42 complexed with the GTPase binding domain of PAK. Nat.Struct.Biol. 7:384

Mott, H.R. et al.(2003) Structure of the GTPase-Binding domain of Sec5 and Investigation of its Ral-binding Site J.Biol.Chem 278:17053

Owen, D. et al.(2003) Molecular dissection of the interaction between the small G proteins Rac1 and RhoA and Protein Kinase C Related Kinase 1 (PRK1) J.Biol.Chem. 278:50578

Owen, D. and Mott, H.(2005) 'Structural Analysis of Rho Protein Complexes' Protein and Cell Regulation (Rho Family GTPases) 3:31

Elliot-Smith, A.E. et al.(2005) Specificity Determinants on Cdc42 for binding its effector protein ACK Biochemistry 44:12373

Elliot-Smith, A.E. et al.(2007) Double mutant cycle thermodynamic analysis of the hydrophobic Cdc42-ACK protein:protein interaction Biochemistry 46:14087

Modha, R. et al.(2008) The Rac1 Polybasic Region Is Required for Interaction with Its Effector PRK1 J.Biol.Chem. 283:1492

Owen, D. et al.(2008) The IQGAP1-Rac1 and IQGAP1-Cdc42 Interactions: Interfaces differ between the complexes J.Biol.Chem. 283:1692

Mott, H.R. and Owen, D.(2009) 'Structure of Rho Family Targets' Handbook of Cell Signalling 2:1827

Fenwick, R.B. et al.(2010) The RalB-RLIP76/RalBP1 complex reveals a novel mode of Ral-effector interaction. Structure 18:985

Hutchinson, C.L. et al.(2011) Mutational analysis reveals a single binding interface between RhoA and its effector, PRK1. Biochemistry 50:2860

Rajasekar, K.V. et al.(2013) The structure of the RLIP76 (RalBP1) RhoGAP domain-Ral binding domain dyad: fixed position of the domains leads to dual engagement of small G proteins at the membrane. Structure 21:2131

Hutchinson, C.L. et al.(2013) Differential binding of RhoA, B and C to the PRK isoforms PRK1, 2 and 3: PRKs have highest affinity for RhoB. Biochemistry 52:7999

Mott, H.R.&Owen, D.(2014) Structure and Function of RLIP76 (RalBP1): an intersection point between Ras and Rho signalling. Biochemical Society Transactions 42:52

Campbell, L. et al.(2015) Thermodynamic mapping of effector protein interfaces with RalA and RalB. Biochemistry 54:1380

Mott, H.R.&Owen, D. (2015) Ras superfamily Effector Complexes: What have we learned in two decades? Critical Reviews in Biochemistry and Molecular Biology 50:85




How good is research at University of Cambridge in Biological Sciences?

FTE Category A staff submitted: 189.63

Research output data provided by the Research Excellence Framework (REF)

Click here to see the results for all UK universities

Email Now

Insert previous message below for editing? 
You haven’t included a message. Providing a specific message means universities will take your enquiry more seriously and helps them provide the information you need.
Why not add a message here
* required field
Send a copy to me for my own records.
Email Sent

Share this page:

Cookie Policy    X