Control of cell shape and motility requires integration of multiple signals that ultimately influence polymerization of the actin cytoskeleton. The WASP protein (for Wiskott-Aldrich syndrome protein, defects in which cause thrombocytopenia, eczema, and immunodeficiency in humans) interacts with the small guanosine triphosphatase Cdc42 and phosphatidylinositol 4,5-bisphosphate (PIP2), which are both mediators of signaling pathways that cause alterations in the actin cytoskeleton. WASP also interacts with the actin-related protein 2/3 (Arp2/3) complex, which stimulates actin nucleation. Prehoda et al. examined how the WASP protein processes multiple inputs to coordinate the activity of Arp2/3 and actin polymerization. Their results indicate that N-WASP (neuronal WASP) exists in a "closed" state, in which Arp2/3 is bound but inactive, and the binding sites for Cdc42 and Arp2/3 are inaccessible. Binding of either Cdc42 or PIP2 appears to promote an active conformation. Activation by Cdc42 and PIP2 is highly cooperative, and thus WASP can function as a "coincidence detector" or "logical AND gate" that is highly activated when it receives signals from both Cdc42 and PIP2. Fawcett and Pawson discuss the results in a Perspective.
Prehoda, K.E., Scott, J.A., Mullins, R.D., and Lim, W.A. (2000) Integration of multiple signals through cooperative regulation of the N-WASP-Arp2/3 complex. Science 290: 801-806 [Abstract] [Full Text]
Fawcett, J. and Pawson, T. (2000) N-WASP regulation--the sting in the tail. Science 290: 725-726. [Full Text]