Welch Group

Welch Group
Welch Group

Research Summary

We study molecular mechanisms that control the Rac protein family, which regulates cell shape, cell movement, oxygen radical formation and gene expression. In particular, we study the proteins that activate Rac, so-called Rac-GEFs. A few years ago, we discovered a new type of Rac-GEF, the P-Rex family, and we have been studying the mechanisms that regulate their activity and their functional roles.

We found that P-Rex family Rac-GEFs are important for the ability of our white blood cells to defend us against bacterial and fungal infections, for the shape and electrical functions of nerve cells that control the coordination of our movements, and for the distribution of skin pigment cells during development. We also participated in studies which showed that the deregulation of the cellular amount or activity of P-Rex family Rac-GEFs contribute to cancer growth and metastasis.

Currently, our lab is investigating new functional roles of P-Rex and other Rac-GEFs, particularly in inflammatory cells, and we are inventing new ways of monitoring Rac-GEF activity.

Latest Publications

Johansen VBI, Hampson E, Tsonou E, Pantarelli C, Chu JY, Crossland L, Okkenhaug H, Massey AJ, Hornigold DC, Welch HCE, Chetwynd SA Signalling, Imaging

Norbin is an adaptor protein that binds numerous G protein-coupled receptors (GPCRs), is highly expressed in neurons, and is essential for a functioning nervous system in rodent models. Yet, beyond its control of neurite outgrowth and synaptic plasticity, few cellular roles of Norbin have been investigated to date. Furthermore, while Norbin is known to regulate the steady-state cell surface levels of several GPCRs, only in one case has the protein been shown to control the agonist-induced receptor internalisation which serves to attenuate GPCR signalling. Here, we generated a Norbin-deficient PC12 cell line which enabled us to study both the cellular functions of Norbin and its roles in GPCR trafficking and signalling. We show that Norbin limits cell size and spreading, and is required for the growth, viability and cell cycle progression of PC12 cells. We also found that Norbin regulates both the steady-state surface level and agonist-induced internalisation of the GPCR sphingosine-1-phosphate receptor 1 (S1PR1) in these cells, suggesting that its role in agonist-dependent GPCR trafficking is more widespread than previously appreciated. Finally, we show that Norbin limits the S1P-stimulated activation of Akt and p38 Mapk, and is required for the activation of Erk in PC12 cells. Together, our findings provide a better understanding of the cellular functions of Norbin and its control of GPCR trafficking.

+view abstract Scientific reports, PMID: 37880240 25 Oct 2023

Machin PA, Johnsson AE, Massey EJ, Pantarelli C, Chetwynd SA, Chu JY, Okkenhaug H, Segonds-Pichon A, Walker S, Malliri A, Fukui Y, Welch HCE Signalling, Bioinformatics, Imaging

Rac-GTPases and their Rac-GEF activators play important roles in neutrophil-mediated host defence. These proteins control the adhesion molecules and cytoskeletal dynamics required for neutrophil recruitment to inflamed and infected organs, and the neutrophil effector responses that kill pathogens.

+view abstract Frontiers in immunology, PMID: 37383235 2023

Lawson CD, Hornigold K, Pan D, Niewczas I, Andrews S, Clark J, Welch H Signalling, Bioinformatics

P-Rex1 and P-Rex2 are guanine-nucleotide exchange factors (GEFs) that activate Rac small GTPases in response to the stimulation of G protein-coupled receptors and phosphoinositide 3-kinase. P-Rex Rac-GEFs regulate the morphology, adhesion and migration of various cell types, as well as reactive oxygen species production and cell cycle progression. P-Rex Rac-GEFs also have pathogenic roles in the initiation, progression or metastasis of several types of cancer. With one exception, all P-Rex functions are known or assumed to be mediated through their catalytic Rac-GEF activity. Thus, inhibitors of P-Rex Rac-GEF activity would be valuable research tools. We have generated a panel of small-molecule P-Rex inhibitors that target the interface between the catalytic DH domain of P-Rex Rac-GEFs and Rac. Our best-characterized compound, P-Rex inhibitor 1 (PREX-in1), blocks the Rac-GEF activity of full-length P-Rex1 and P-Rex2, and of their isolated catalytic domains, at low-micromolar concentration, without affecting the activities of several other Rho-GEFs. PREX-in1 blocks the P-Rex1 dependent spreading of PDGF-stimulated endothelial cells and the production of reactive oxygen species in fMLP-stimulated mouse neutrophils. Structure-function analysis revealed critical structural elements of PREX-in1, allowing us to develop derivatives with increased efficacy, the best with an IC of 2 µM. In summary, we have developed PREX-in1 and derivative small-molecule compounds that will be useful laboratory research tools for the study of P-Rex function. These compounds may also be a good starting point for the future development of more sophisticated drug-like inhibitors aimed at targeting P-Rex Rac-GEFs in cancer.

+view abstract Small GTPases, PMID: 36342857 Jan 2022

Group Members

Heidi Welch

Group Leader

Stephen Chetwynd

Postdoc Research Scientist

Julia Chu

Postdoc Research Scientist

Priota Islam

PhD Student

Valdemar Johansen

Visiting Student