Disease relevance of PAK7

• In N1E-115 neuroblastoma cells, expression of PAK5 also triggered the induction of neurite-like processes, and a dominant-negative PAK5 mutant inhibited neurite outgrowth [1].

High impact information on PAK7

• Previously, we have shown that Pak5 localizes primarily to mitochondria [2].
• To study the relationship between Pak5 localization and its effects on apoptosis, we identified three N-terminal regions that regulate the localization of this kinase: a mitochondrial targeting sequence, a nuclear export sequence, and a nuclear localization sequence [2].
• Moreover, blockade of nuclear export with leptomycin B causes endogenous Pak5 to accumulate in the nucleus [2].
• These results show that Pak5 shuttles from mitochondria to the nucleus and that the mitochondrial localization of Pak5 is vital to its effects on cell survival [2].
• Finally, we show that reduction of endogenous Pak5 expression in neuroblastoma and neural stem cells increases their sensitivity to apoptosis and that this effect is reversed upon reexpression of wild-type Pak5 but not of a mutant form of Pak5 that cannot localize to mitochondria [2].

Biological context of PAK7

• When the first two sequences are deleted, Pak5 is retained in the nucleus and no longer protects cells from apoptosis [2].
• These features make Pak5 unique among the Pak family and suggest that it plays an important role in apoptosis through BAD phosphorylation [3].
• p21-activated kinase 5 (Pak5) is an effector for the small GTPase Cdc42, known to activate cell survival signaling pathways [2].
• The inhibition requires the binding between the PAK5 and MARK2 catalytic domains, but does not require phosphorylation [4].
• Although MARK2 transfected alone destabilizes microtubules and stabilizes actin stress fibers, PAK5 keeps microtubules stable through the down-regulation of MARK2 but destabilizes the F-actin network so that stress fibers and focal adhesions disappear and cells develop filopodia [4].

Anatomical context of PAK7

• PAK5, a new brain-specific kinase, promotes neurite outgrowth in N1E-115 cells [1].
• We have found that PAK5, like Cdc42, promotes the induction of filopodia [1].
• PAK5 kinase is an inhibitor of MARK/Par-1, which leads to stable microtubules and dynamic actin [4].
• Thus, MARK and its regulators MARKK and PAK5 appear to mediate the crosstalk between the actin and microtubule cytoskeleton in an antagonistic fashion [5].

Associations of PAK7 with chemical compounds

• On the other hand, mutation of tyrosine 40 to cysteine of Cdc42 did not knockout the binding of Pak5 [6].
• In the present study, we have purified the glutathione S-transferase fusion form of Pak5 and shown for the first time that Pak5 autophosphorylation can be activated by GTP bound form of Cdc42 [6].

Regulatory relationships of PAK7

• PAK5 suppresses the activity of MARK2 toward its target, tau protein [4].

Other interactions of PAK7

• Here we summarize recent findings that shed light on the newly recognized Group II Paks (Pak4, Pak5, Pak6) and review both similarities and differences between kinases of the two Pak subgroups [7].
• The results point to an inverse relationship between actin- and microtubule-related signaling by the PAK5 and MARK2 pathways that affect both cytoskeletal networks [4].

Analytical, diagnostic and therapeutic context of PAK7

• PAK5 transcript is predominantly expressed in brain as revealed by Northern blot and in situ hybridization [8].

References