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Growth Factor Signalling

Group Site: 
oxford
Group Leader: 

Alex N. Bullock

Group Info

Research Areas

Growth Factor Signalling

The normal development of our tissues, body shape and size is strictly coordinated.  Secreted growth hormones and cytokines signal between cells to regulate the key physiological processes of growth and differentiation as well as responses to injury and infection.  These signalling pathways are also implicated in many diseases.  Inappropriate growth control is a defining feature of human cancer, and is frequently associated with constitutive kinase activation.  Excessive cytokine (interferon and interleukin) responses also underlie autoimmune and inflammatory diseases, such as rheumatoid arthritis, diabetes and asthma.  Alternatively, in some cases growth factor deficiencies can be managed by protein therapies, for example growth hormone (GH), insulin and interferon.

Kinase activation

The SGC is addressing how growth factor signals are propagated inside the cell by phosphorylation.  Classically, growth factor binding to transmembrane receptors activates receptor (RTK) and non-receptor (PTK) protein tyrosine kinases to create intracellular docking sites for the recruitment of SH2 effector proteins (e.g. GRB2, STATs) leading to downstream signalling and transcription.  Similarly, TGFβ/BMP receptor serine kinases (RSK) recruit SMAD MH2 domains for the control of stem cell fate and tissue morphogenesis.  Tumour cells with constitutive kinase activation, resulting from mutation or overexpression, may gain growth factor-independent proliferation and form a target for directed kinase inhibitors. 

In 1998 the HER-2-specific antibody Herceptin was launched against breast cancer and became the first approved treatment directed against a growth factor kinase. The further discovery of potent and specific Abl tyrosine kinase inhibitors, such as Gleevec, which is approved for the treatment of chronic myeloid leukaemia, has raised considerable hope for further drug therapies.  Working together with the phosphorylation-dependent Signalling group we have identified anti-leukemic inhibitors of the PIM1 survival kinase that is known to be essential for v-Abl transformation.

E3 ubiquitin ligases

Phosphorylation is a principal control switch for kinase and receptor recognition by E3 ubiquitin ligases.  E3 ligases can direct the internalization or degradation of substrate proteins by the transfer of ubiquitin and thereby suppress the amplitude and duration of growth factor Signalling.  Dysregulation of E3 ligases, such as Cbl which degrades EGFR, can produce a variety of immune diseases, diabetes and cancer.  However, with some 500 human E3 family members there is still much to understand about their structure, mechanism and specificity.   The ubiquitin-proteasome system is also a new area for drug design.  The general proteasome inhibitor Bortezomib shows selective toxicity for tumour cells and is approved for the treatment of myeloma.  With their substrate specificity, E3 ligases provide opportunities for more directed therapies, but the availability of suitable druggable sites remains in question.  The stabilization of p53 by the Mdm2-inhibitor Nutlin offers a promising proof of principle.

Target area

We are extending our early studies of the PIM1 proto-oncogene to other signalling kinases, working closely with the phosphorylation dependent Signalling group.  These studies address the structure, regulation and specificity of protein kinases as well as their potential for drug design.  We are particularly interested in the TGFβ/BMP receptor serine kinases for which we receive funding support from Roemex and the University of Oxford FOP Research Fund.  We have solved the crystal structures of five of the twelve receptor kinases in this family and identified a potent BMP inhibitor with specificity for the ACVR1 (ALK2) kinase.

Work is also directed against multi-protein RING-type E3 ligases of the F-box, BTB and SOCS box families which bind cullins 1, 3 and 5, respectively.  The suppressor of cytokine Signalling (SOCS) family comprises eight SH2 protein members identified initially as specific feedback inhibitors of JAK/STAT Signalling.  We have determined complex structures of the SOCS2, SOCS4 and SOCS6 E3 ligases, defining their respective specificity for GHR, EGFR and c-KIT, as well as their similar domain organization to the VHL E3 ligase.

Structures

Overview of GFS Group Structures

Group Members
Alex Bullock, PhD

Alex obtained his BA and PhD at the University of Cambridge where he worked with Sir Alan Fersht on the misfolding of mutant p53. He won a Wellcome Trust International Prize Travelling Research Fellowship which he held first with David Baker at the University of Washington, Seattle and later with Peter Ratcliffe at the University of Oxford, where he studied protein interactions in the HIF-1α hypoxia pathway. He joined the SGC for its launch in 2004 working initially with Stefan Knapp. He established the growth factor signaling group in 2008.

Georgina Mosedale, PhD

George undertook her PhD studies with Dr KJ Patel at the MRC LMB in Cambridge.  Subsequently, she moved to the Weatherall Institute of Molecular Medicine in Oxford for postdoctoral work in the group of Dr Ian Hickson.  At SGC, George is funded by a Roemex fellowship for cellular work on BMP signaling in the rare bone disease fibrodysplasia ossificans progressiva (FOP).

Peter Canning, PhD

Peter studied Biochemistry at the University of Warwick and stayed to join the Structural Biology group for his PhD on the structure of peptidases, which he completed in 2009. He subsequently joined the GFS group at the SGC to further his interest in high throughput crystallography.  His first structure for the group was the DNA-binding domain of p73.

Eleanor Williams, PhD

Ellie graduated from the University of Oxford and subsequently completed her PhD studies working on Hsp90 with Prof John Ladbury at UCL.  At SGC, Ellie is funded by a Roemex fellowship for work on BMP signaling in the the rare bone disease fibrodysplasia ossificans progressiva (FOP).  She is studying how BMP receptors assemble and has worked on structures of human endofin and  the kinase ACVR2A (ActRIIA).

Vikram Ayinampudi, MSc

Vikram obtained his MSc from the University of Edinburgh and joined the GFS group in 2009.  His first structure for the group was the N-terminal domain of Cullin5.  He has also starred in the department of medicine cricket team.

Caroline Sanvitale, BSc(Hons)

Caroline obtained her BSc in Biochemistry from the University of Sussex and joined the SGC in 2009 to begin a DPhil to understand the activation of ACVR1 in the rare bone disease fibrodysplasia ossificans progressiva (FOP).  Her studentship at Green Templeton College is funded by the University of Oxford FOP Research Fund.  Caroline’s work has led to various structures of the ACVR1 and BMPR1B receptor kinases.

Sarah Dixon-Clarke, BSc(Hons)

Sarah obtained her BSc from the School of Biology at the University of St Andrews where she undertook research projects on inhibitors of HSP90 and monoamine oxidase. She subsequently won a prestigious NDM Prize DPhil studentship and started her DPhil in Oxford in October 2011. Her work addresses the structure and function of the extended CDK-cyclin family, in particular CDK16-18.  These kinases have a proposed role in neurite outgrowth, neuronal migration and brain development.

Publications

Publications of Alex Bullock and the GFS group (2005-2011)


2011

  • Gregson CL, Hollingworth P, Williams M, Petrie KA, Bullock AN, Brown MA, Tobias JH, Triffitt JT. (2011). A novel ACVR1 mutation in the glycine/serine-rich domain found in the most benign case of a fibrodysplasia ossificans progressiva variant reported to date. Bone. [Epub ahead of print]
  • Fedorov O, Huber K, Eisenreich A, Filippakopoulos P, King O, Bullock AN, Szklarczyk D, Jensen LJ, Fabbro D, Trappe J, Rauch U, Bracher F, Knapp S. (2011). Specific CLK Inhibitors from a Novel Chemotype for Regulation of Alternative Splicing. Chem Biol. 18, 67-76.
  • Zadjali F, Pike AC, Vesterlund M, Sun J, Wu C, Li SS, Rönnstrand L, Knapp S, Bullock AN, Flores-Morales A. (2011). Structural basis for c-KIT inhibition by the suppressor of cytokine signaling 6 (SOCS6) ubiquitin ligase. J Biol Chem. 286, 480-90.

2010

  • Filippakopoulos P, Low A, Sharpe TD, Uppenberg J, Yao S, Kuang Z, Savitsky P, Lewis RS, Nicholson SE, Norton RS, Bullock AN. (2010). Structural basis for Par-4 recognition by the SPRY domain- and SOCS box-containing proteins SPSB1, SPSB2, and SPSB4. J Mol Biol. 401, 389-402.
  • López-Ramos M, Prudent R, Moucadel V, Sautel CF, Barette C, Lafanechère L, Mouawad L, Grierson D, Schmidt F, Florent JC, Filippakopoulos P, Bullock AN, Knapp S, Reiser JB, Cochet C. (2010). New potent dual inhibitors of CK2 and Pim kinases: discovery and structural insights. FASEB J. 24, 3171-85.

2009

2008

2007

2006

2005

Contact

alex [dot] bullock[at]sgc [dot] ox [dot] ac [dot] uk (Dr. Alex Bullock)

SGC
University of Oxford
Old Road Campus Research Building (ORCRB)
Roosevelt Drive
Headington
Oxford  OX3 7DQ
UK

Tel: +44 (0) 1865 617754

Alumni

Former Group Members


Timothy Sharpe, PhD

Tim completed his studies at the University of Oxford before moving to Cambridge to work on protein folding in the group of Sir Alan Fersht. He joined SGC in 2008 and worked on three structures including the E3 ligase SPSB2. He moved on to work with Prof Chris Abell.


Chancievan Thangaratnarajah, BSc

Chancie completed his studies at the University of Westminster. He joined the SGC in 2008 to gain lab experience before undertaking his PhD studies. He crystallised the BMPR2 kinase in complex with ADP, providing valuable insights into disease mutations associated with pulmonary arterial hypertension. He moved on to work with Prof Frances Ashcroft.


Ewa S. Pilka, DPhil

Ewa finished her Masters degree in Biotechnology at the University of Gdansk, Poland. She came to Oxford to complete her DPhil in protein NMR and subsequently trained in crystallography as a post-doctoral researcher at the LMB, University of Oxford. She joined SGC in January 2005 and moved to the GFS group in 2010. She obtained diffraction quality crystals of the middle domain of human HSP90β before taking up a position in industry at Evotec.


Ivan Alfano, PhD

Ivan worked jointly for the Phosphorylation Dependent Signalling and Growth Factor Signalling groups. He led efforts in both groups in baculoviral expression of human kinases. His first structure for the GFS group was the ACVR1-FKBP12 protein complex and defined the binding mode of the BMP-selective inhibitor dorsomorphin. Ivan has returned to his beloved Italy.


Viktorija Hojzan, MSc

Viktorija completed her MSc at the University of Oxford in the Metabolic Enzymes group of Dr Udo Oppermann. She joined the GFS group in 2010. Her work led to the structure of the kelch domain of KLHL2. Viktorija has moved on to work with Prof. Nenad Ban at ETH Zurich.

Kunde Guo, PhD

Kunde joined SGC in 2004 as a team leader in protein engineering. He moved from the Metabolic Enzymes group of Dr Udo Oppermann to the GFS group in 2010.  His work on RNG-type E3 ligases led to structures for CBLB and CBLC as well as the ASB9-ElonginC-ElonginB complex.  Kunde retired from SGC in September 2011.

Visiting Scientists

Alessandra Beltrami (Freie Universität Berlin)

Alessandra obtained an EMBO Short-Term Fellowship to visit SGC for 3 months in the autumn of 2010 as part of her PhD studies.