Our group studies the control of cell growth, the role of insulin-like molecules in growth and other cellular and physiological processes, and the cellular mechanisms of signalling by insulin-like molecules (here referred to as insulin signalling).  Insulin and insulin-like growth factors have fundamental roles in nutrient-regulated metabolism and growth.  Indeed, defective signalling by these molecules is known to be a critical factor in both diabetes and many forms of human cancer.  However, many of the genes regulating the cellular response to insulin have not yet been identified.

Powerful genetic approaches in the fruit fly Drosophila melanogaster have allowed our group and others to demonstrate important new functions for the insulin signalling cascade (for example, in cell growth and control of lifespan), and to show that the branch of the insulin signalling pathway involving the kinases PI3-kinase and Akt/PKB is a key regulator of growth and the TOR signalling cascade.  TOR is an evolutionarily ancient kinase that in yeast and higher eukaryotes responds to local extracellular nutrients, particularly amino acids.  Thus this local nutrient-sensitive system appears to have been hijacked by the endocrine nutrient-regulated insulin system in multicellular organisms to control processes like cellular growth.

In the last two years, our group has made a number of additional breakthroughs in the genetic dissection of the insulin signalling cascade and growth regulation.  Our primary tool is genetic screening.  We identify new genes that control cellular growth or metabolism and genetically interact with the insulin signalling cascade; we use a series of screens that require simple genetic crosses and very little time at the bench, allowing us to find new regulators in screens involving hundreds of candidate genes.  Equally important, the genes that we find often reveal novel mechanisms by which insulin controls cell functions that we can then analyse in detail.

Current Research Programme

How do cellular nutrient sensors interact with the insulin signalling cascade?

A collaboration between Deborah Goberdhan, Richard Boyd, David Meredith (all in this department) and my group has identified a specific class of amino acid transporters – the proton-assisted amino acid transporters (or PATs) – as unique regulators of TOR, growth, insulin signalling and insulin resistance in flies.  More recent work has confirmed that mammalian PATs can also have the same effects.  PATs can potentially function in multiple cellular compartments, including the plasma membrane, endosomes and lysosomes, and this may provide an important link to insulin signalling (see below). 

We also have some evidence that PAT signalling may not require transport of amino acids, raising the possibility that these molecules are members of a new class of molecules known as ‘transceptors’.  Since PATs can both promote TOR-dependent overgrowth and cellular insulin resistance, we have established collaborations with clinical groups to determine whether these molecules have a key role to play in cancer and diabetes.

How does subcellularly restricted cell surface Akt control cell morphology?

A collaboration between Franck Pichaud’s group (University College London), Deborah Goberdhan and my lab has revealed that epithelial cells control apical surface morphology through very precise hyperactivation of Akt specifically within the apical domain.  This is achieved by targeting both activating and inhibitory components of the PI3-kinase signalling cascade in specific positions within and adjacent to the apical domain.  Localised Akt activation appears to regulate vesicle trafficking to and from the cell surface (see below), a mechanism that may be important in controlling apical morphology in many epithelial cell types.  We are currently studying other molecules which may be involved in this process.

How does cytoplasmic activated Akt control lipid metabolism and insulin resistance?

Recent work in the lab has identified a highly evolutionarily conserved regulatory protein phosphatase subunit that specifically controls levels of activated cytoplasmic Akt.  While Akt near the cell surface is a well-established regulator of growth and glucose transport, we have found that cytoplasmic Akt has a different range of functions, most notably controlling lipid storage and transcriptional/translational regulatory programmes that may induce insulin resistance. 

This work has led us to propose a new model in which cellular sensitivity to insulin can be differentially controlled in different subcellular domains to regulate different insulin-dependent functions.  However, it has also opened up new avenues to genetically dissect insulin-controlled lipid storage mechanisms in the fly.  Furthermore, in our system we can very easily test how lipid storage in one tissue can affect insulin sensitivity in others, allowing us to study how obesity in flies might modulate insulin resistance.

Insulin signalling, vesicle trafficking and the actin cytoskeleton: a common functional link?

Many of the molecules emerging from our genetic screens for regulators of insulin-dependent growth are linked to control of the actin cytoskeleton and vesicle trafficking.  Insulin is known to regulate cell surface shuttling of glucose transporters and our hypothesis is that processes like cellular growth may also be regulated by insulin-dependent shuttling of transporters like the PATs.  Interestingly, TOR and its putative upstream regulators have a well established role in transporter trafficking in yeast and, in collaboration with Deborah Goberdhan, we are testing whether similar mechanisms exist in higher organisms.

Are new genes controlling insulin signalling and lipid storage involved in insulin-linked diseases?

We directly collaborate with Mark McCarthy’s group at the Oxford Centre for Endocrinology, Diabetes and Metabolism, who screen the homologues of new regulators of insulin signalling emerging from our screens for variability in patients suffering from Type II diabetes

Other growth regulators: how does the ski family of oncogenes control growth?

The fly homologue of the ski/sno family of oncogenes was identified in our growth regulatory genetic screens.  We have shown that like its mammalian counterparts, it strongly inhibits the TGF-β signalling cascade when overexpressed, and that this is the primary mechanism by which it controls growth. However, surprisingly its normal roles are much more restricted because of genetic redundancy with other TGF-β signalling antagonists.  Several other growth regulators have been identified in our screens, which we hope to analyse in more detail over the next few years.

Other areas of interest and overlap: insulin signaling and the nervous system

A small group of neurons in each hemisphere of the fly brain secrete insulin-like molecules in a nutrient-dependent manner to control organismal growth.  These neurons therefore share some of the functions of pancreatic β-cells.  We are using genetic tools to screen candidate (i.e. transporters, channels or their regulators) or novel genes involved in the secretory process.

In addition, we also collaborate with Kay Davies group to study the role of the Drosophila homologue of transcription factor AF4, Lilliputian, in growth and neuronal survival, two processes that are also regulated by insulin signalling. Based on this work, we have started to examine the role of insulin signalling in the nervous system, particularly in the control of neuronal survival, since this pathway has been suggested to play a role in certain human neurodegenerative disorders, such as Parkinson’s disease.

Clive Wilson