Mechanisms of WASp regulation. (A) Schematic representation of WASp autoinhibition. The VCA domain binds a region from residues 242 to 310, which includes the C-terminal part of the CRIB domain.¹¹  The minimal high-affinity Cdc42 binding site is WASp 230 to 288.^12,13 (B) WASp is capable of interpreting signals from many different inputs. These inputs may regulate WASp directly and determine its subcellular localization (see “Regulation of WASp activity”). All regulators/modifications shown activate WASp/N-WASp activity in vitro, with the exception of WIP, which inhibits activation by Cdc42. However, this inhibition may be reversed in the presence of Cdc42–Toca-1 leading to enhanced N-WASp/WASp activity.¹⁴  The zigzag lines on PIP₂, Cdc42, and protein tyrosine kinases (PTKs) represent lipid modifications responsible for membrane localization. Adaptor proteins such as Nck may also act through WIP to localize WASp. The interplay between these signals remains an important area of study. +++ indicates basic region; 2 indicates SH2 domain; 3 indicates SH3 domain; adaptor indicates, for example, Nck, Grb2, syndapin, intersectin, and PSTPIP1 (proline, serine, threonine-rich phosphatase interacting protein 1); P, phosphate; pink arrows, pathway leading to regulation (or production) of signaling molecule; hatched arrows, phosphorylation events; and solid gray arrows, direct interactions.