p21-activated protein kinase 2 (PAK-2) is a member of the p21-activated protein kinase (PAK) family of serine/threonine kinases. PAKs are activated by the p21 G-proteins Rac or Cdc42 in response to a variety of extracellular signals and act in pathways controlling cell growth, cell shape, cell motility, cell survival and cell death. PAK-2 is unique among the PAK family because it is also activated through proteolytic cleavage by caspase 3 or similar proteases to generate the constitutively active PAK-2p34 fragment. Activation of full-length PAK-2 by Rac or Cdc42 stimulates cell survival and protects cells from cell death whereas caspase-activated PAK-2p34 induces a cell death response. Caspase-activated PAK-2p34 but not full-length PAK-2 is rapidly degraded by the 26S proteasome. Stabilization of PAK-2p34 by preventing its poly-ubiquitination and degradation results in a dramatic stimulation of cell death. Although many proteins have been shown to interact with and regulate full-length PAK-2, little is known about the regulation of caspase-activated PAK-2p34. Here, we identify PS-GAP as a regulator of caspase-activated PAK-2p34. PS-GAP is a GTPase-activating protein for Cdc42 and RhoA which was originally identified by its interaction with the tyrosine kinase PYK-2. PS-GAP interacts specifically with caspase-activated PAK-2p34 but not with active or inactive full-length PAK-2 through a region between the GAP and SH3 domains. The interaction with PS-GAP inhibits the protein kinase activity of PAK-2p34 and changes the localization of PAK-2p34 from the nucleus to the perinuclear region. Furthermore, PS-GAP decreases the stimulation of cell death induced by stabilization of PAK-2p34.