Disease relevance of PKN1

• A novel inducible transactivation domain in the androgen receptor: implications for PRK in prostate cancer [1].
• Using the amino-terminal regulatory domain of PKN as a bait, cDNA encoding a neural antigen PCD17, which is recognized by characteristic antibodies of patients with paraneoplastic cerebellar degeneration, was isolated from a human brain cDNA library [2].
• As the mouse mutation myodystrophy myd has been mapped to the same region, Prkcl1 is a candidate gene for myd [3].
• A Salmonella type III secretion effector interacts with the mammalian serine/threonine protein kinase PKN1 [4].
• Here we show that Opa52-expressing gonococci or Escherichia coli or F(ab) fragments directed against CD66, respectively, activate a signalling cascade from CD66 via Src-like protein tyrosine kinases, Rac1 and PAK to Jun-N-terminal kinase [5].

Psychiatry related information on PKN1

• Finally, PKN and Cdc25C colocalize to the nuclear region only during the critical period of time prior to entry into the M phase [6].
• The concentration of protein kinase C-like immunoreactivity was reduced in Alzheimer's disease samples, although the protein kinase C activity determined by the phosphorylation of exogenous histone was not [7].

High impact information on PKN1

• When activated by extracellular signals via membrane signaling receptors, Rac executes its functions through engaging downstream effectors such as p21-activated kinase (PAK), a serine/threonine protein kinase [8].
• In this issue, report direct communication between guanylyl cyclases and the Rac-p21-activated kinase (PAK) signaling pathway-which is essential for cell migration-to promote cell motility, through allosteric activation of guanylyl cyclases by autophosphorylated PAK [9].
• This Rac/PAK/GC/cGMP pathway is involved in platelet-derived growth factor-induced fibroblast cell migration and lamellipodium formation [8].
• Consequently, Nef, but not a Nef mutant incapable of activating PAK, blocked apoptosis in T cells induced by serum starvation or HIV replication [10].
• MLCK activity and MLC phosphorylation were decreased, and cell spreading was inhibited in baby hamster kidney-21 and HeLa cells expressing constitutively active PAK1 [11].

Chemical compound and disease context of PKN1

• In addition, tamoxifen stimulation led to up-regulation of ER target genes in breast cancer cells with increased Pak1 expression [12].
• NF-kappaB- and C/EBPbeta-driven interleukin-1beta gene expression and PAK1-mediated caspase-1 activation play essential roles in interleukin-1beta release from Helicobacter pylori lipopolysaccharide-stimulated macrophages [13].
• HIV infection of AMs (as a model for reduced mannose receptor expression and function) was associated with impaired F-actin polymerization, reduced Cdc42 and Rho activation, and markedly reduced PAK-1 phosphorylation in response to Pc organisms [14].
• Rac activity, phosphorylation levels of PAK1/2, and p44/42 MAPK were assessed in cultures treated with or without nicotine after multiple wounds [15].
• Estrogen regulation of Pak1 and FKHR pathways in breast cancer cells [16].

Biological context of PKN1

• A role for PKN1 in mediating arsenite-induced G(2)/M delay was supported by the finding that expression of a constitutively active form of PKN1 (PKN1AF3) in HeLa cells delayed the mitotic entry of cell cycle [17].
• The transactivation unit 5 (TAU-5) located in the N-terminus of AR suffices for activation by PRK1 [1].
• Phosphorylation events associated with different states of activation of a hepatic cardiolipin/protease-activated protein kinase. Structural identity to the protein kinase N-type protein kinases [18].
• PKN is a fatty acid- and Rho-activated serine/threonine protein kinase, having a catalytic domain homologous to protein kinase C family [19].
• Sigmoidal autophosphorylation kinetics and increased S6-(229-239) peptide kinase activity following preincubation with ATP suggested phosphorylation-dependent activation of PAK-1/PKN [18].

Anatomical context of PKN1

• Cardiolipin- or protease-activated protein kinase, isolated from rat liver cytosol and originally named liver PAK-1, was found to be the natural form of protein kinase N (PKN) by comparing the sequences of 43 tryptic peptides of the purified liver enzyme and determining the corresponding liver cDNA sequence [18].
• Both PRK1 and PRK2, expressed in COS 1 cells, are autophosphorylated in immunoprecipitates, indicating intrinsic kinase activity [20].
• Here, we present evidence that identifies a novel plasma membrane pool of PRK1 [21].
• The phosphorylation of serine377 of PRK1 is required for its integration into membranes [21].
• PKN, a fatty acid- and Rho-activated serine/threonine kinase having a catalytic domain highly homologous to protein kinase C (PKC), was cleaved at specific sites in apoptotic Jurkat and U937 cells on Fas ligation and treatment with staurosporin or etoposide, respectively [22].

Associations of PKN1 with chemical compounds

• PKN1 is a serine/threonine protein kinase that has been reported to mediate cellular response to stress [17].
• Together, our results suggest that PKN1 mediates arsenite-induced delay of the G(2)/M transition by binding to and phoshorylating Cdc25C [17].
• Importantly, PRK signalling also stimulates AR activity in the presence of adrenal androgens, which are still present in prostate tumour patients subjected to testicular androgen ablation therapy [1].
• PCD17 was phosphorylated by PKN, and the extent of this phosphorylation was enhanced by addition of 40 microM arachidonic acid [2].
• The activation of both Rac1 and Pak1 by 8-Br-cGMP was completely abolished by transfection of the cells with G1alphaR-GFP [23].
• Instead, we found that protein kinase C-related kinase, a Rho-dependent serine/threonine kinase, is activated in endothelial cells upon thrombin stimulation and that its expression is required for endothelial permeability and the remodeling of cell-extracellular matrix and cell-cell adhesions [24].

Physical interactions of PKN1

• Here we report the 2.2 A crystal structure of RhoA bound to an effector domain of protein kinase PKN/PRK1 [25].
• PKN bound to the third spectrin-like repeats of both skeletal and non-skeletal muscle type alpha-actinin [19].
• PKN interacts with a paraneoplastic cerebellar degeneration-associated antigen, which is a potential transcription factor [2].

Enzymatic interactions of PKN1

• In addition to a direct interaction, PDK1 also phosphorylated Thr(774) in the activation loop and activated PKN [26].
• HPr kinase/phosphorylases (HprKs) regulate catabolite repression and sugar transport in Gram-positive bacteria by phosphorylating the small phosphotransferase system (PTS) protein HPr on a serine residue [27].

Regulatory relationships of PKN1

• PRK1 (PKN) is a serine/threonine kinase that has been shown to be activated by RhoA (Amano, M., Mukai, H., Ono, Y., Chihara, K., Matsui, T., Hamajima, Y., Okawa, K., Iwamatsu, A., and Kaibuchi, K. (1996) Science 271, 648-650) [28].
• PKN regulates phospholipase D1 through direct interaction [29].
• Analysis of the activation state of the components upstream of p38 and JNK showed that NSAIDs inhibit the serine-threonine kinase p21-activated protein kinase 1 (Pak1) and the small guanosine 5'-triphosphatase (GTPase) Rac, as well as the Rac-specific guanine nucleotide exchanger, Vav [30].
• Moreover, Cdc25C is phosphorylated by the TGF-beta1-activated PKN [6].
• Past work described the partial purification and characterization of a novel serine protein kinase activity designated protein kinase N (PKN) that is activated by nerve growth factor (NGF) in cultured PC12 cells [Rowland et al. (1987) J. Biol. Chem. 262; 7504-7513] [31].

Other interactions of PKN1

• Multiple interactions of PRK1 with RhoA. Functional assignment of the Hr1 repeat motif [28].
• Interaction of PKN with alpha-actinin [19].
• These results suggest that the PKN family functions as a novel intracellular player of PLD1 signaling pathway [29].
• Here we investigate the binding of PRK1 to RhoA and Rac1, two members of the Rho family [32].
• PRK1 and PRK2, as well as a third member of this family, PRK3, show distinct patterns of expression in adult tissues [20].

Analytical, diagnostic and therapeutic context of PKN1

• We found by FISH that PRKCL1 is localized to chromosome 19p12-p13.1 and, more precisely, by radiation hybrid mapping, about 11 cR from EST WI-6344 in subband 19p12 [3].
• We determined the chromosomal location of the human PKN gene PRKCL1 by fluorescence in situ hybridization and by radiation hybrid mapping [3].
• Immunofluorescence analysis of HeLa cells revealed that CG-NAP was localized to centrosome throughout the cell cycle, the midbody at telophase, and the Golgi apparatus at interphase, where a certain population of PKN and RIIalpha were found to be accumulated [33].
• Our results suggest that therapeutic strategies that suppress PAK-mediated survival signals may improve the efficacy of current cancer chemotherapies by enhancing p38 MAPK-mediated cell death [34].
• Co-immunoprecipitation experiments revealed that mouse AWP1 specifically interacts with a rat serine/threonine protein kinase PRK1 in vivo [35].

References