Regulation of actin assembly by the WAVE complex
Background
Regulation of the actin cytoskeleton is crucial for cell morphology and motility during development, health and disease. In motile cells, actin assembly occurs largely by nucleation of new actin filaments on the sides of existing filaments to generate branched filament networks that push and deform the plasma membrane, causing protrusion of the leading edge. The Arp2/3 complex is a key factor mediating nucleation and branching of filaments, and it is regulated by nucleation promoting factors such as WASP, N-WASP and WAVE proteins. Upstream signals, initiated by ligands binding to growth factor or chemoattractant receptors, recruit nucleation promoting factors to the plasma membrane, where they stimulate actin nucleation by the Arp2/3 compex.
Prior Actin Research in the Lab
In the past few years, the lab has been studying the mechanisms whereby N-WASP and WAVE integrate upstream signals and stimulate the activity of the Arp2/3 complex. Important breakthroughs were made in understanding the regulation of N-WASP by the small GTPase Cdc42, phosphoinositides such as PIP2, and the PCH family protein TOCA-1. The crucial discovery that WAVE proteins form large heteropentameric complexes also opened up new possibilities for understanding their regulation. However, how these complexes regulate WAVE function is still poorly defined.
My Current Research
I am using primarily biochemical approaches in experimental systems ranging from Xenopus egg and leukocyte extracts to in vitro actin assembly reactions with defined components to study the mechanisms regulating WAVE complex activity.