The very C-terminus of PRK1/PKN is essential for its activation by RhoA and downstream signaling

Lim, Wee Guan; Tan, Bee Jen; Zhu, Yimin; Zhou, Shu‐Feng; Armstrong, James B.; Li, Qiu Tian; Dong, Qihan; Chan, Eli; Smith, D. J.; Verma, Chandra; Tan, Seng‐Lai; Duan, Wei

doi:10.1016/j.cellsig.2005.11.009

Cited by 14 publications

(9 citation statements)

References 31 publications

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“…Recently, Lim et al (32)(33)(34) described that the PRK C terminus is required for the activation by Rho and that it is additionally involved in the regulation of PRKs by lipids. However, it is not yet clear how this is related to the regulatory mechanisms we have observed in this work.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the Interaction between Protein Kinase C-related Protein Kinase 2 (PRK2) and Its Upstream Kinase, 3-Phosphoinositide-dependent Protein Kinase 1 (PDK1)

Dettori

Sonzogni

Meyer

et al. 2009

Journal of Biological Chemistry

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The members of the AGC kinase family frequently exhibit three conserved phosphorylation sites: the activation loop, the hydrophobic motif (HM), and the zipper (Z)/turn-motif (TM) phosphorylation site. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates the activation loop of numerous AGC kinases, including the protein kinase C-related protein kinases (PRKs). Here we studied the docking interaction between PDK1 and PRK2 and analyzed the mechanisms that regulate this interaction. In vivo labeling of recombinant PRK2 by 32 P i revealed phosphorylation at two sites, the activation loop and the Z/TM in the C-terminal extension. We provide evidence that phosphorylation of the Z/TM site of PRK2 inhibits its interaction with PDK1. Our studies further provide a mechanistic model to explain different steps in the docking interaction and regulation. Interestingly, we found that the mechanism that negatively regulates the docking interaction of PRK2 to the upstream kinase PDK1 is directly linked to the activation mechanism of PRK2 itself. Finally, our results indicate that the mechanisms underlying the regulation of the interaction between PRK2 and PDK1 are specific for PRK2 and do not apply for other AGC kinases.The regulation of protein function by phosphorylation and dephosphorylation is a key mechanism of intracellular signaling pathways in eukaryotic organisms. Protein phosphorylation is catalyzed by protein kinases, which are themselves often regulated by phosphorylation (1). The specificity of protein kinases is essential for their cellular functions. In some groups of protein kinases, the specificity is achieved by means of "docking interactions." Protein kinase docking interactions involve a recognition site on the kinase or a flanking domain that is different from the active site. The most notable example, MAP kinases, uses a docking interaction to specifically recognize substrates, upstream kinases, and phosphatases. Despite the large amount of data on protein kinase docking interactions, e.g. in the MAP kinase field, there is very little information on how these essential interactions are regulated (2-4).3-Phosphoinositide-dependent protein kinase 1 (PDK1) 3 belongs to the AGC family of protein kinases and is the activation loop kinase for several other AGC kinases (5). A key feature of the AGC kinase family members except PDK1 is the presence of a C-terminal extension (CT) to the catalytic core that contains a conserved hydrophobic motif (HM) harboring a phosphorylation site. In many AGC kinases, the HM mediates a docking interaction with PDK1. For example, p90 ribosomal S6 kinase (RSK), p70 S6 kinase (S6K) and serum-and glucocorticoid-induced protein kinase (SGK) interact with PDK1 upon phosphorylation of the HM site (6 -9). The phosphorylated HM binds to a HM-binding pocket in the catalytic core of PDK1 that was originally termed the PIF-binding pocket (6, 10). Besides its role in the docking of substrates to PDK1, the HM/PIF-binding pocket was also identified as a ubiquitous and key regulator...

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Section: Discussionmentioning

confidence: 99%

Regulation of the Interaction between Protein Kinase C-related Protein Kinase 2 (PRK2) and Its Upstream Kinase, 3-Phosphoinositide-dependent Protein Kinase 1 (PDK1)

Dettori

Sonzogni

Meyer

et al. 2009

Journal of Biological Chemistry

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“…All 3 isoforms contain three polybasic coiled-coiled motifs the first two of which as elucidated for PKN1 and 2, bind to Rac- and Rho GTPases [4], [5], [6], [7]. Furthermore, the very C-termini of PKN1 and 2 also play a role in binding to RhoA [8], [9]. In addition, PKN1 responds to phosphoinositides [10] and fatty acids such as arachidonic, linoleic and oleic acid [11], [12], [13]; these properties differ for PKN2 [14].…”

Section: Introductionmentioning

confidence: 99%

Regulatory Domain Selectivity in the Cell-Type Specific PKN-Dependence of Cell Migration

et al. 2011

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The mammalian protein kinase N (PKN) family of Serine/Threonine kinases comprises three isoforms, which are targets for Rho family GTPases. Small GTPases are major regulators of the cellular cytoskeleton, generating interest in the role(s) of specific PKN isoforms in processes such as cell migration and invasion. It has been reported that PKN3 is required for prostate tumour cell invasion but not PKN1 or 2. Here we employ a cell model, the 5637 bladder tumour cell line where PKN2 is relatively highly expressed, to assess the potential redundancy of these isoforms in migratory responses. It is established that PKN2 has a critical role in the migration and invasion of these cells. Furthermore, using a PKN wild-type and chimera rescue strategy, it is shown that PKN isoforms are not simply redundant in supporting migration, but appear to be linked through isoform specific regulatory domain properties to selective upstream signals. It is concluded that intervention in PKNs may need to be directed at multiple isoforms to be effective in different cell types.

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“…Both lobes are connected by a hinge region. The catalytic domain is located between both terminal lobes and shows high conservation and similarity to the PKC family kinase domain [21,22]. Moreover, PRK1 and PKC are members of AGC kinase family [23].…”

Section: Structural Analysis Of Prk1mentioning

confidence: 99%

Application of Computer Modeling to Drug Discovery: Case Study of PRK1 Kinase Inhibitors as Potential Drugs in Prostate Cancer Treatment

Najjar¹,

Ntie‐Kang²,

Sippl³

2017

Unique Aspects of Anti-Cancer Drug Development

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Computer modeling of natural products (NPs) and NP scaffolds is increasingly gaining importance in drug discovery, particularly in hit/lead discovery programs and at the lead optimization stage. Even though industry had lost interest in the implication of NPs in hit/lead searches, recent reports still show that computer modeling could be a useful assert for the identification of starting scaffolds from nature, which could be further exploited by synthetic modifications. In this chapter, the focus is on some useful tools for computer modeling aimed at the discovery of anticancer drugs from NP scaffolds. We also focus on some recent developments toward the identification of potential anticancer agents by the application of computer modeling. The chapter will lay emphasis on natural sources of anticancer compounds, present some useful databases and computational tools for anticancer drug discovery, and show some recent case studies of the application of computational modeling in anticancer drug discovery, as well as some success stories in virtual screening applications in anticancer drug discovery, highlighting some useful results on the application of on lead discovery (including promising NP scaffolds) against an interesting anticancer drug target, the protein kinase C-related kinase (PRK1).

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The very C-terminus of PRK1/PKN is essential for its activation by RhoA and downstream signaling

Cited by 14 publications

References 31 publications

Regulation of the Interaction between Protein Kinase C-related Protein Kinase 2 (PRK2) and Its Upstream Kinase, 3-Phosphoinositide-dependent Protein Kinase 1 (PDK1)

Regulation of the Interaction between Protein Kinase C-related Protein Kinase 2 (PRK2) and Its Upstream Kinase, 3-Phosphoinositide-dependent Protein Kinase 1 (PDK1)

Regulatory Domain Selectivity in the Cell-Type Specific PKN-Dependence of Cell Migration

Application of Computer Modeling to Drug Discovery: Case Study of PRK1 Kinase Inhibitors as Potential Drugs in Prostate Cancer Treatment

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