Alan Hall

Alan Hall FRS (19 May 1952 – 3 May 2015) was a British cell biologist and a biology professor at the Sloan-Kettering Institute, where he was chair of the Cell Biology program.

Hall's PhD was on the enzymology of B-lactamase, which led to his first paper being published in Nature in 1976.

He used strains of E. Coli with mutated B-lactamase, an antibiotic resistance enzyme, and assayed their activity in the presence of Benzylpenicillin and Cephalosporin C. Direct selection on these mutants allowed catalytic properties of B-lactamase to be identified and allowed structure-function relationships of the enzyme to be further researched.

He began his studies for a PhD at Oxford, but after two months he followed his major professor Jeremy R. Knowles to Harvard University, where he earned a PhD in biochemistry in 1977.

He then took postdoctoral fellowships in molecular biology at the University of Edinburgh and the University of Zurich.

In 1981 he went to work at Institute for Cancer Research in London, where he stayed for 12 years.

His work, in collaboration with his colleague and close friend Christopher Marshall, made seminal contributions to our understanding of cell signalling in animal cells, in particular the role of Rho and Ras small GTPases in regulating a variety of cellular functions such as proliferation, morphology and migration.

In 1982, Hall helped identify transforming sequences in human sarcoma cells lines at the Institute for Cancer Research in London.

DNA from a rhabdomyosarcoma cell line and a fibrosarcoma cell line transformed a NIH/3T3 mouse fibroblast cell line.

After injection into mice, tumors started to form in as little as 10 days.

Next, the transforming activities of the rhabdomyosarcoma and fibrosarcoma cell lines were measured after being digested with an array of endonucleases.

Further DNA testing showed that the transforming sequences in the two cancer cell lines were the same, and the gene was later characterised as N-ras, a member of the Ras gene family.

In 1986, Hall helped uncover properties of the human p21 protein, which is encoded by N-ras.

GTPase activity of different mutant forms of p21, one cloned from a patient with myeloblastic leukaemia and one derived from in vitro mutagenesis, was measured.

Results showed no correlation between the wild-type or mutant N-ras p21's GTPase activity and transforming potential.

These findings were published in Molecular and Cellular Biology (MCB).

Alan Hall showed the specificity of Rho in the stimulation of focal adhesions and stress fibres formation in fibroblasts in the presence of extracellular factors in 1992.

He first realised that the addition of bovine fetal calf serum (FCS) to Swiss 3T3 cells increased the polymerisation of actin and assembly of stress fibres.

The immunofluorescence following the increase of vinculin and talin, two cytoskeletal proteins, at the intracellular face of the plasma membrane with Val14rhoA microinjection showed the association of focal adhesions with the end of the new stress fibres.

After size fractionation of FCS and analysis of the lipids that bound to serum albumin, the lysophosphatidic acid (LPA) was found to be responsible for the serum activity that induced stress fibre formation.

The inhibition of Rho by C3 transferase ribosylation resulted in an inhibition of focal adhesion and stress fibre assembly, but had no effect on membrane ruffling.

These findings were published in Cell and cited over 4000 times.

In parallel with this experiment, Hall showed that the presence of Rac, another Ras-related GTP-binding protein, is implicated in the regulation of the actin organisation in presence of extracellular growth factors.

Immunofluorescence and antibody techniques were used to localise the mutant V12rac1 protein after being microinjected into the cytoplasm of confluent serum-starved Swiss 3T3 cells.

The comparison with the normal cells showed that Rac1 stimulates actin filament production at the membrane, pinocytosis, and membrane ruffling.

The inhibition of endogenous Rac function by mutants N17rac and V12rac1 prevented growth factor-induced membrane ruffling.

In addition, the inactivation of Rho protein by ADP-ribosylation in Rac1 microinjection reduced the formation of actin stress fibres.

Hall concluded that Rac and Rho are complementary for polymerised actin organisation.

Indeed, Rho-dependent response is stimulated by the action of growth factors on Rac protein.

In 1993 he moved to University College London, where he helped to create a new MRC centre for molecular cell biology.

Hall was elected a Fellow of the Royal Society in 1999.

Hall was born in Barnsley in Yorkshire.

He earned his BA in chemistry from Oxford University.

In 2000, he became director of that program.

In 2002, Alan Hall discerned the role of Gaq in Rho signalling pathways.

Prior to this publication, there were conflicting reports as to the role of Gaq in cell signalling via Rho; some said that it was not able to induce Rho activation, and some said that it could.

Using immunoblotting techniques, Hall showed that activation of endogenous Gaq via G protein-coupled receptors (GCPRs) could in fact induce activation of Rho, and had similar results when directly expressing activated Gaq.

It was already known that other Ga proteins could induce Rho activation (i.e. Ga13 activates p115 Rho GEF, which in turn activates Rho), but it was also known that Gaq does not activate p115 Rho GEF, and therefore must act via an alternate, unknown mechanism.

Two years later, he moved to Memorial Sloan Kettering Cancer Center as chair of the cell biology program.

In 2005, there was an abundance of activators and targets of the Rho pathway that had been identified, yet very little investigation into the way in which specificity of the pathway is maintained.