Signal Integration Signaling Through an AND Gate

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]