We have two main interests, macropinocytosis and chemotaxis, which are both driven by the actin cytoskeleton and signalling at the plasma membrane.
Macropinocytosis was the first endocytic process to be discovered, but is the least well understood. It is used by free-living amoebae for feeding: Dictyostelium cells can take up droplets of nutrient-rich medium into internal vesicles called macropinosomes. This medium is processed through an internal digestive system and soluble nutrients extracted. Macropinocytosis is evolutionarily conserved and adapted by immune cells to sample for foreign antigens in their environment and can be hijacked by pathogens as a way of entering cells. Most surprisingly it appears that cancer cells can also feed by macropinocytosis and that it is used by prion proteins to spread in the brain.
Macropinosomes form by the closure of cups driven out from the plasma membrane by a ring of polymerizing actin. Macropinocytic cups are self-organizing structures across a scale of several microns. They form around patches of intense Ras and PIP3 signalling, whose size is controlled by the tumour suppressor, NF1 (neurofibromatosis-1), which inactivates Ras. We have proposed a ‘template hypothesis’ for macropinocytic cup formation, in which nucleators of actin polymerization are recruited to the periphery of the Ras/PIP3 patches, but not to their centre. We want to identify further components of these patches, find how they assemble, and how they are regulated by NF1.
Cells move by extending their leading edge using either pseudopods or blebs, and can be guided to their destinations by many different environmental signals, including gradients of attractive chemicals. Pseudopods and blebs seem to be advantageous for moving in different environments, with blebs preferred when cells face mechanical resistance. We are trying to understand how cells sense mechanical resistance and so favour bleb-driven migration. We are also interested in how blebs and pseudopods are orientated to the front of cells by chemotactic gradients and have found that chemotactic signalling activates a master protein kinase, which phosphorylates a core set of regulatory proteins common to different chemoattractants.
We have earlier interests in genomics, polyketide signalling and sex determination in Dictyostelium.