High impact information on PAK4

• We also show that the phosphatase activity of purified SSH-1L is F-actin dependent and is negatively regulated via phosphorylation by PAK4 [1].
• We here present a novel cell motility pathway by demonstrating that PAK4 directly interacts with an integrin intracellular domain and regulates carcinoma cell motility in an integrin-specific manner [2].
• Furthermore, we mapped the PAK4 binding to the membrane-proximal region of integrin beta 5, and identified an integrin-binding domain at aa 505-530 in the COOH terminus of PAK4 [2].
• Functionally, PAK4 induced integrin alpha v beta 5-mediated, but not beta1-mediated, human breast carcinoma cell migration, while no changes in integrin cell surface expression levels were observed [2].
• Thus, unlike other members of the PAK family, PAK4 provides a novel link between Cdc42Hs and the actin cytoskeleton [3].

Biological context of PAK4

• Because cell survival is a key part of tumorigenesis and anchorage-independent growth, we studied whether PAK4 has a role in protecting cells from cell death [4].
• Although most previous work was carried out with overexpressed PAK4, here we used RNA interference to knock down endogenous PAK4 in cancer cells [4].
• Furthermore, dominant negative LIMK1 and a mutant cofilin inhibited the specific cytoskeletal and cell shape changes that were induced in response to a recently characterized constitutively activated PAK4 mutant [5].
• The cellular locations of PAK4 and Cdc42Hs suggest a role for the Golgi in cell morphogenesis [3].
• Activated PAK4 regulates cell adhesion and anchorage-independent growth [6].

Anatomical context of PAK4

• Its expression is elevated in many cancer cell lines, and activated PAK4 is highly transforming, suggesting that it plays an important role in tumorigenesis [4].
• By studying PAK4 knockdown HeLa cells, we demonstrated that endogenous PAK4 is required for anchorage-independent growth [4].
• Importantly, the reorganization of the actin cytoskeleton is dependent on PAK4 kinase activity and on its interaction with Cdc42Hs [3].
• PAK4, a novel effector for Cdc42Hs, is implicated in the reorganization of the actin cytoskeleton and in the formation of filopodia [3].
• Most importantly, fibroblasts expressing activated PAK4 had a morphology that was characteristic of oncogenic transformation [6].

Associations of PAK4 with chemical compounds

• PAK4 is the most recently identified member of the PAK family of serine/threonine kinases [5].
• Co-expression of PAK4 and the constitutively active Cdc42HsV12 causes the redistribution of PAK4 to the brefeldin A-sensitive compartment of the Golgi membrane and the subsequent induction of filopodia and actin polymerization [3].

Physical interactions of PAK4

• PAK4 was shown to interact specifically with LIMK1 in binding assays [5].
• Our results indicate that PAK4 is required for optimal binding of the scaffold protein TRADD to the activated TNFalpha receptor through both kinase-dependent and kinase-independent mechanisms [4].

Regulatory relationships of PAK4

• Here we show that PAK4 also regulates the activity of the protein kinase LIM kinase 1 (LIMK1) [5].

Other interactions of PAK4

• PAK5 is structurally most related to PAK4 and PAK6 to make up the PAK-II subfamily [7].
• In contrast, the group 2 PAKs (PAK4, 5, and 6) lack this autoinhibitory domain and are not activated by Cdc42/Rac binding, and the mechanisms that regulate their kinase activity have been unclear [8].
• Immunofluorescence experiments revealed that PAK4 and LIMK1 cooperate to induce cytoskeletal changes in C2C12 cells [5].
• Consequently, activation of several prosurvival pathways, including the NFkappaB and ERK pathways, is reduced in the absence of PAK4 [4].
• To address this, we studied the role for PAK4 downstream to the tumor necrosis factor (TNF) alpha receptor [4].

References