Actin Nucleation by ARP-WASP Complex

For many cell types, the ability to move across a solid surface is fundamental to their biological function. Certain aspects of cell locomotion, such as the protrusion of plasma membrane in lamellipodia and filopodia, are driven by the polymerization of actin cytoskeleton. The actin cytoskeleton is a dynamic filament network that is essential for cell movement during embryonic development, polarization, morphogenesis, cell division, immune system function and in the metastasis of cancer cells. To accomplish these varied cellular activities, tight spatial and temporal control is exerted over several aspects of the actin polymerization cycle, including the nucleation of new actin filaments and the elongation of existing ones. Members of the Wiskott-Aldrich Syndrome Protein (WASP) family such as N-WASP and at least three variants of SCAR/WAVE (WAVE 1, 2, 3) play a central role in regulating these processes.Nucleation of new actin filaments is spatially controlled by the actin-related protein (ARP2/3) complex. This complex is important for the initiation of actin assembly in several cellular processes and it can nucleate a branched network of actin filaments at the leading edge of cells. This pushes the plasma membrane forward and causes protrusions. ARP2/3 complex is stimulated upstream by extracellular signals transmitted through growth factors, RTKs, GPCRs and integrins. The Rho family GTPase Rac is an important mediator of ARP2/3 activation. All members of the WASP family contain a carboxyl-terminal verprolin homology, cofilin homology, and acidic region (VCA) domain that binds and activates the ARP2/3 complex, thereby linking these proteins to the induction of actin polymerization.Mutations in the WASP gene results in Wiskott-Aldrich Syndrome, an immune system disorder. Other related disorders such as thrombocytopenia, eczema, and immunodeficiency also exist due to specific mutations in WASP, which alter its activity.