Heidi Welch
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• Recent, selected Publications

Signalling via P-Rex family guanine-nucleotide exchange factors

The Rho family of small GTPases are intracellular molecular switches that control a wide range of a cell’s responses, ranging from gene expression to cell migration, to signals received either from the outside or from within the cell. The GTPases are switched on by a family of enzymes called guanine-nucleotide exchange factors, or GEFs, that are sensitive to these signals. Our work is aimed at understanding the functional roles and the mechanisms of regulation of one particular family of GEFs, the P-Rex family, which activates the Rho-family GTPase, Rac.

Figure 1 (Click to enlarge)

Shape of the endothelial PAE cell line
without (top) or with (bottom) active Rac.

The small GTPase, Rac, regulates a range of important cellular functions, including transcription, translation, cell survival, cytoskeletal structure, adhesion, and cell motility (Figure 1). In neutrophils, Rac additionally regulates reactive oxygen species formation, chemotaxis, degranulation and phagocytosis. Rac deficiency in neutrophils reduces our ability to clear bacterial and fungal infections.

Figure 2 (Click to enlarge)

The chemoattractant fMLP stimulates primed neutrophils to produce reactive oxygen species. P-Rex1 is necessary for this response.

We have identified a family of direct activators of Rac, the P-Rex family GEFs (1). We found P-Rex1 in neutrophils (1), and have shown it is involved in regulating G protein-coupled receptor-dependent Rac2 activation, production of reactive oxygen species (Figure 2), chemotaxis, and neutrophil recruitment to inflammatory sites (2).
We have also addressed the mechanisms of regulation of P-Rex1. We found that P-Rex1 is activated by the lipid second messenger PtdIns(3,4,5)P3 and by the βγ subunits of heterotrimeric G proteins (1). Mutagenesis revealed that P-Rex1 is activated via its PH domain by PtdIns(3,4,5)P3 and via its catalytic DH domain by Gβγ subunits (3) (Figure 3).

Figure 3 (Click to enlarge)

Regulation of P-Rex1 enzyme activity. PtdIns(3,4,5)P3
activates P-Rex1 via the PH domain.

We have also identified and characterised a homologue of P-Rex1, P-Rex2, which has a different tissue distribution than P-Rex1 but has the same substrate specificity and mode of regulation (4). One current project is our investigation of the functional importance of P-Rex2.


Recent, selected publications

Barber MA, Donald S, Thelen S, Anderson KE, Thelen M, Welch HCE (2007) Membrane translocation of P-Rex1 is mediated by G protein βγ subunits and phosphoinositide 3-kinase.
Journal of Biological Chemistry 282 29967-29976
http://dx.doi.org/10.1074/jbc.M701877200

Barber MA, Welch HCE (2006) PI3K and RAC signalling in leukocyte and cancer cell migration.
Bulletin du Cancer 93 E44-E52
http://www.jle.com/en/revues/medecine/bdc/e-docs/00/04/1B/06/article.md?type=text.html

Hill K, Krugmann S, Andrews SR, Coadwell WJ, Finan P, Welch HCE, Hawkins PT, Stephens LR (2005) Regulation of P-Rex1 by phosphatidylinositol(3,4,5)-trisphosphate and Gβγ subunits.
Journal of Biological Chemistry 280 4166-4173
http://dx.doi.org/10.1074/jbc.M411262200

Welch HCE, Condliffe AM, Milne LJ, Ferguson GJ, Hill K, Webb LMC, Okkenhaug K, Coadwell WJ, Andrews SR, Thelen M, Jones GE, Hawkins PT, Stephens LR (2005) P-Rex1 regulates neutrophil function.
Current Biology 15 1867-1873
http://dx.doi.org/10.1016/j.cub.2005.09.050

Donald S, Hill K, Lecureuil C, Barnouin R, Krugmann S, Coadwell WJ, Andrews SR, Walker SA, Hawkins PT, Stephens LR, Welch HCE (2004) P-Rex2, a new guanine-nucleotide exchange factor for Rac.
FEBS Letters 572 172-176
http://dx.doi.org/10.1016/j.febslet.2004.06.096

Welch HCE, Coadwell WJ, Stephens LR, Hawkins PT (2003) Phosphoinositide 3-kinase-dependent activation of Rac.
FEBS Letters 546 93-97
http://dx.doi.org/10.1016/S0014-5793(03)00454-X

Welch HCE, Coadwell WJ, Ellson CD, Ferguson GJ, Andrews SR, Erdjument-Bromage H, Tempst P, Hawkins PT, Stephens LR (2002) P-Rex1, a PtdIns(3,4,5)P3- and Gβγ-regulated guanine-nucleotide exchange factor for Rac.
Cell 108 809-821
http://dx.doi.org/10.1016/S0092-8674(02)00663-3