Small G proteins and their effectors as therapeutic targets in cancer at University of Cambridge on FindAPhD.com

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Dr Darerca Owen Applications accepted all year round Competition Funded PhD Project (Students Worldwide)

Cambridge United Kingdom Biochemistry Cancer Biology Cell Biology Molecular Biology

About the Project

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 along with their role in cellular signaling cascades. We have determined several structures (by NMR) of small G proteins (primarily of the Rho and Ras families) in complex with the G protein binding regions 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 for therapeutic purposes. We are now using this information to generate lead therapeutic peptides. We also have a major programme of work currently underway to delineate the role of the Cdc42 effector and tyrosine kinase, ACK, in tumourigenesis.

Funding Notes

Applicants should hold or be about to achieve a First or Upper-Second (2.i) class degree in a relevant subject.

MRC-DTP and BBSRC_DTP studentships are available to eligible students (UK nationals and EU students who meet the UK residency requirements).
https://mrcdtp.medschl.cam.ac.uk/
https://bbsrcdtp.lifesci.cam.ac.uk/

Biochemistry Departmental AstraZeneca studentships are also available to UK/EU nationals.

CRUK Cambridge Centre studentships are available to UK/EU students and international students through the Cellular and molecular biology programme https://crukcambridgecentre.org.uk/studentships

Applicants with full funding from a competitive source of any nationality 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. and 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 and Owen, D. (2015) Ras superfamily Effector Complexes: What have we learned in two decades? Critical Reviews in Biochemistry and Molecular Biology 50: 85

Watson, J.R. et al. (2016) Investigation of the Interaction Between Cdc42 and its Effector TOCA1: Handover of Cdc42 to the Actin Regulator N-WASP is Facilitated by Differential Binding Affinities. J. Biol. Chem. 291: 13875

Thomas, J.T. et al. (2016) Inhibition of Ral GTPases using a stapled peptide approach. J. Biol. Chem. 291: 18310

Watson, J.R. et al. (2016) Cdc42 in actin dynamics: An ordered pathway governed by complex equilibria and directional effector handover. Small GTPases 7:1

Tetley, G.J.N. et al. (2017) A dock and coalesce mechanism driven by hydrophobic interactions governs Cdc42 binding with its effector protein ACK. J. Biol. Chem. 292: 11361

Mott, H.R. and Owen D. (2018) Bioblockades join the assault on small G protein signaling. Seminars in Cancer Biology (doi.org/10.1016/j.semcancer.2018.01.001)

Owen D. and Mott, H.R. (2018) CRIB effector disorder: exquisite function from chaos. Biochemical Society Transactions 46: 1289

Tetley, G.J.N. et al. (2018) Bond swapping from a charge cloud allows flexible co-ordination of upstream signals through WASP: Multiple regulatory roles for the WASP basic region. J. Biol. Chem. 293: 15136

Mott, H.R. and Owen D. (2018) Allostery and dynamics in small G proteins. Biochemical Society Transactions 46: 1333