Research Group

Julie Pitcher Research Group

1985 BSc in Biochemistry, Oxford University
1989 PhD in Biochemistry, University of Dundee
Julie Pitcher
Tel: 020 7679 7950
Fax: 020 7679 7805
Awards: 
1999 Wellcome Trust senior Research Fellowship
Previous Posts: 
1989-1995 Postdoctoral Fellow, Duke University, NC, USA
1996-1999 Research Assistant Professor, Duke University, NC, USA
1999-2006 Group Leader, MRC Laboratory for Molecular Cell Biology and Dept of Pharmacology, UCL
2006- Senior lecturer in Pharmacology UCL

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G-protein-coupled receptors (GPCRs) represent the largest family of cell surface receptors. They share a common 7 transmembrane domain configuration and act to transduce extracellular stimuli to the interior of the cell. GPCRs are expressed in virtually every cell type and modulate an extremely wide range of physiological processes. They represent a rich source of targets for the pharmaceutical industry with approximately 30-50% of current pharmaceuticals targeting these proteins.
Following repeated or continuous exposure to agonists GPCRs exhibit diminished responsiveness, a phenomenon termed receptor desensitisation. For many GPCRs rapid desensitisation is mediated by a family of serine/threonine kinases, the G protein-coupled receptor kinases (GRKs). GRKs phosphorylate agonist-occupied GPCRs and the phosphorylated receptor serves as a binding site for a member of the arrestin family. Arrestin binding uncouples the GPCR from G proteins and targets the phosphorylated receptor for internalisation via clathrin-coated pits. Given their role in regulating GPCR function it is not surprising that changes in the expression levels, or activities, of the GRKs are associated with a number of disease states. For example, elevated levels of GRK2 and 5 are responsible for alterations in myocardial function in chronic heart failure.

In addition to their role in mediating GPCR desensitisation several lines of evidence suggest the GRKs have other cellular functions. It is our aim to elucidate at the molecular level the cellular functions of the GRKs, work which may aid in the design of therapeutically useful GRK inhibitors.

Current/future projects include:

1) Investigating potential nuclear functions of the GRKs

The GRK family is divided into three subfamilies based on sequence similarity. The GRK1 (GRKs 1 and 7); GRK2 (GRKs 2 and 3); and GRK4 (GRKs 4, 5 and 6) subfamilies. We have discovered that members of the GRK4 subfamily contain functional nuclear localisation and nuclear export sequences (NLSs and NESs). These observations led to the hypothesis that these kinases may have nuclear functions. Indeed, cardiac expression of GRK5 was shown to promote pathological cardiac hypertrophy in vivo via a mechanism that’s dependent on its nuclear localisation. GRK5 acts as a class II histone deacetylase (HDAC) kinase because it can associate with and phosphorylate the myocyte enhancer factor-2 repressor, HDAC5. GRK5 is upregulated in human pressure overload disease suggesting that it may play a causative role in disease progression and thus represent a potential therapeutic target. Additional nuclear functions of GRK5, and other members of the GRK4 subfamily, are currently being investigated (see Katrina Lester).

2) GRKs as G protein effectors

Common structural features of the GRKs include an RGS homology (RH) domain in their amino-termini and HR1 Rho-binding repeats within their catalytic domain. The ligand for the RH domain of GRK2 has been identified as GqGTP. Notably, in contrast to most other RGS-containing proteins GRK2 fails to GAP GqGTP. These observations suggest the GRKs may serve as effectors for both heterotrimeric and small G proteins. Indeed, we have identified GRK2 as a Rho-activated MAPK scaffold, and are currently investigating other potential G protein-dependent functions of the GRK family (see James Robinson).

3) The identification of novel binding partners and functions for the GRKs and arrestins

Numerous proteins have been shown to interact with the GRKs and the arrestin family of adaptor proteins. Recently we have identified the clathrin adaptor AP1 and the small GTPase ARF1 as arrestin1 binding partners. These observations suggest intracellular trafficking roles for this member of the arrestin family a hypothesis currently being explored within the laboratory (see Kathleen Webb).

4) The identification of GRK family specific inhibitors.

We aim to use high throughput screening approaches to identify novel inhibitors for this family of kinases. The screens will be performed in collaboration with the Translational Research Resource Centre, MRC Laboratory for Molecular Cell Biology (LMCB) & Cell Biology Unit.