Disease relevance of Pkn1

• Identification of two eukaryote-like serine/threonine kinases encoded by Chlamydia trachomatis serovar L2 and characterization of interacting partners of Pkn1 [1].
• CT145 and CT301 (encoding Pkn1 and PknD, respectively) were expressed in Escherichia coli as GST fusion proteins [1].
• Finally, we found that consistent with a role in breast tumor progression, Pak1 expression and its nuclear accumulation was increased progressively during the transition from ductal hyperplasia to ductal carcinoma in situ to adenocarcinoma in widely used multistep polyoma-middle T-antigen transgenic mice [2].
• Emerging data suggest that p21-activated kinase 1 (Pak1), a downstream signaling molecule of the small GTPases, growth factors, and lipid signaling, is upregulated or hyperactivated in human breast cancer [2].
• Our results showed that in a transgenic mouse model, overexpression of catalytically active Pak1 leads to the development of malignant mammary tumors and to a variety of other breast lesions, including focal solid nodules, ductal hyperplasia, and mini-intraductal neoplasm and adenoma [2].

High impact information on Pkn1

• These observations indicate that PKA and PAK are important regulators of anchorage-dependent signal transduction [3].
• The integrin-binding protein Nischarin regulates cell migration by inhibiting PAK [4].
• Temporal and spatial distribution of activated Pak1 in fibroblasts [5].
• Platelet-derived growth factor stimulation of NIH-3T3 cells shows a pattern of Pak1 activation similar to that observed with Rac1 [5].
• Expression of constitutively activated Pak1 was accompanied by increased myosin light chain (MLC) phosphorylation, whereas expression of kinase-dead Pak1 had no effect on MLC [6].

Biological context of Pkn1

• Associated with vesicle recruitment, PKN1 is shown to undergo activation loop phosphorylation and activation [7].
• These results suggest that Pak1 affects the phosphorylation state of MLC, thus linking this kinase to a molecule that directly affects cell movement [6].
• Furthermore, Rac1 deletion led to a marked increase in spontaneous apoptosis that could be rescued by active PAK1, AKT, or MEK1 expression [8].
• Here, we show that Pak1 is phosphorylated during mitosis in mammalian fibroblasts [9].
• In lower eukaryotes, Pak1 homologs are regulated during the cell cycle by phosphorylation [9].

Anatomical context of Pkn1

• We show that PSMA inhibition, knockdown, or deficiency decreases endothelial cell invasion in vitro via integrin and PAK, thus abrogating angiogenesis [10].
• During closure of a fibroblast monolayer wound, Pak1 is rapidly activated and localizes to the leading edge of motile cells, then gradually tapers off as the wound closes [5].
• In contrast, cells expressing a kinase-dead form of Pak1 projected multiple lamellipodia emerging from different parts of the cell simultaneously [6].
• We established clonal tetracycline-regulated NIH-3T3 cell lines that inducibly express either wild-type Pak1, a kinase-dead, or constitutively-active forms of this enzyme, and examined the morphology, F-actin organization, and motility of these cells [6].
• Because cell motility requires polarized rearrangements of the actin/myosin cytoskeleton, we examined the role of Pak1 in regulating cell movement [6].

Associations of Pkn1 with chemical compounds

• PKN1 kinase activity is not necessary for this translocation, and in fact the PKN inhibitor HA1077 is also shown to induce PKN1 vesicle accumulation [7].
• Phosphoamino acid analysis by thin-layer chromatography confirmed that Pkn1 and PknD are phosphorylated on both serine and threonine residues [1].
• PAK phosphorylates a conserved serine or threonine residue in the myosin heavy chain [11].
• Expression of a Pak1 mutant in which Thr 212 is replaced with a phosphomimic (aspartic acid) has marked effects on the rate and extent of postmitotic spreading of fibroblasts [9].
• Recently, we have shown that LPA stimulates p21-activated kinase (PAK) that is critical for focal adhesion kinase (FAK) phosphorylation and cell motility [12].

Other interactions of Pkn1

• Taken together, our findings present a pathway for the selective hyperosmotic-induced Rac1-dependent PKN1 translocation and PDK1-dependent activation [7].
• Protein kinase N 1 (PKN1), which in part resembles yeast protein kinase C, has been shown to be under the control of Rho GTPases and 3-phosphoinositide-dependent kinase 1 (PDK1) [7].

Analytical, diagnostic and therapeutic context of Pkn1

• Co-immunoprecipitation experiments demonstrate an in vivo interaction of PAK1 with filamentous (F)-actin in stimulated cells [13].
• Microinjection of a constitutively active PAK1 mutant into Rat-1 fibroblasts overexpressing the insulin receptor (HIRcB cells) induced the formation of F-actin- and PAK1-containing structures reminiscent of dorsal ruffles [13].

References