Topic
PKN3
About: PKN3 is a research topic. Over the lifetime, 6 publications have been published within this topic receiving 267 citations.
Papers
1 Jan 2012
TL;DR: PKN3, a member of the AGC kinase fam-ily, has been identified as a promising, novel therapeutic target in cancer cells for inhibiting tumor progression and lymph node metasta-sis formation and to overcome limitations of chemically synthesized siRNA molecules in vivo.
Abstract: Chemically synthesized, small interfering RNAs (siRNA) are currently used as a new class of therapeutic molecules, allowing the controlled down-regulation of pathologically relevant gene expression e.g., oncogenes and other similar targets in cancer [1, 2, 3].However, the overall negative charge of siRNA molecules (up to 40 negative charg-es) and the relatively high molecular weight (12,000 – 14,000 Da) prevent the functional uptake of these novel therapeutic molecules in vivo. Besides the inefficient uptake and the degradation in endosomal compartments at the cellular level, non-formulated siRNAs are rapidly cleared by renal excretion from the blood stream when administered i.v. [4].To overcome these limitations, a variety of non-viral nanoparticles (50 – 200 nm) have been recently developed enabling chemically synthesized siRNA to be used therapeuti-cally for inhibition of RNAi-mediated tumor growth. Atu027 is a novel RNAi therapeutic agent based on cationic lipoplexes containing chemically stabilized siRNAs, which target Protein Kinase N3 (PKN3) gene expression in the vascular endothelium (Figure 1) [5]. PKN3, a member of the AGC kinase fam-ily, has been identified as a promising, novel therapeutic target in cancer cells for inhibiting tumor progression and lymph node metasta-sis formation [6]. These studies have revealed that PKN3 mediates malignant cell growth downstream of the chronically activated phosphoinositide 3-kinase (PI3K) pathway [6]. Recently, PKN3 has also been considered as a suitable therapeutic target for modulating tumor-associated angiogenesis. Preclinical data, obtained in various cancer mouse mod-els, revealed target-specific, RNAi-mediated silencing of PKN3 expression and significant inhibition of tumor progression and metasta-sis formation [
139 citations
TL;DR: It is demonstrated that PKN3, a barely characterized protein kinase C‐related molecule, is regulated by PI3K at both the expression level and the catalytic activity level, and might represent a preferred target for therapeutic intervention in cancers that lack tumor suppressor PTEN function or depend on chronic activation ofPI3K.
Abstract: Chronic activation of the phosphoinositide 3-kinase (PI3K)/PTEN signal transduction pathway contributes to metastatic cell growth, but up to now effectors mediating this response are poorly defined. By simulating chronic activation of PI3K signaling experimentally, combined with three-dimensional (3D) culture conditions and gene expression profiling, we aimed to identify novel effectors that contribute to malignant cell growth. Using this approach we identified and validated PKN3, a barely characterized protein kinase C-related molecule, as a novel effector mediating malignant cell growth downstream of activated PI3K. PKN3 is required for invasive prostate cell growth as assessed by 3D cell culture assays and in an orthotopic mouse tumor model by inducible expression of short hairpin RNA (shRNA). We demonstrate that PKN3 is regulated by PI3K at both the expression level and the catalytic activity level. Therefore, PKN3 might represent a preferred target for therapeutic intervention in cancers that lack tumor suppressor PTEN function or depend on chronic activation of PI3K.
122 citations
TL;DR: The shows a novel interaction of p130Cas with Ser/Thr kinase PKN3, which is implicated in prostate and breast cancer growth downstream of phosphoinositide 3‐kinase, and suggests that the P KN3–p130Cas complex represents an attractive therapeutic target in late‐stage malignancies.
18 citations
TL;DR: New set of potential PKN3 substrates are identified and a new negative feedback regulatory mechanism of Rho signaling mediated by P KN3-induced ARHGAP18 activation is revealed.
Abstract: Protein kinase N3 (PKN3) is a serine/threonine kinase implicated in tumor progression of multiple cancer types, however, its substrates and effector proteins still remain largely understudied. In the present work we aimed to identify novel PKN3 substrates in a phosphoproteomic screen using analog sensitive PKN3. Among the identified putative substrates we selected ARHGAP18, a protein from RhoGAP family, for validation of the screen and further study. We confirmed that PKN3 can phosphorylate ARHGAP18 in vitro and we also characterized the interaction of the two proteins, which is mediated via the N-terminal part of ARHGAP18. We present strong evidence that PKN3-ARHGAP18 interaction is increased upon ARHGAP18 phosphorylation and that the phosphorylation of ARHGAP18 by PKN3 enhances its GAP domain activity and contributes to negative regulation of active RhoA. Taken together, we identified new set of potential PKN3 substrates and revealed a new negative feedback regulatory mechanism of Rho signaling mediated by PKN3-induced ARHGAP18 activation.
4 citations
TL;DR: It is presented the first report of an interaction between p130Cas with the serine/threonine kinase PKN3, implicated in prostate and breast cancer growth, and the results suggest that the P KN3-p130Cas complex may represent an attractive therapeutic target in late-stage malignancies.
Abstract: Protein p130Cas is an adaptor protein mainly implied in integrin signaling downstream of Src kinase. Due to its modular structure p130Cas acts as a general regulator of cancer cell growth and invasiveness induced by different oncogenes. Besides involvement in integrin-mediated signaling, however, p130Cas signaling leading to malignant progression is not well known. In this study, we show a novel interaction of p130Cas with Ser/Thr kinase PKN3 which is implicated in tumor growth of prostate and breast cancer cells downstream of phosphoinositide 3-kinase. This interaction is direct and is mediated by p130Cas SH3 domain and centrally located polyproline sequence of PKN3. PKN3 is the first Ser/Thr kinase identified not only to bind p130Cas, but also showed to be able to phosphorylate p130Cas in vitro. We demonstrate that PKN3 colocalizes with p130Cas in pro-invasive structures, lamellipodia and podosome rosettes, and that PKN3-p130Cas interaction increases PKN3-driven invasiveness and growth of mouse embryonic fibroblasts (MEFs) and MEFs transformed by Src oncogene. Furthermore, we show the importance of PKN3-p130Cas interaction for tumor growth of Src-transformed cells in vivo. Taken together, our results suggest that the PKN3-p130Cas complex may represent an attractive therapeutic target in late-stage malignancies.
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2020 | 1 |
| 2019 | 1 |
| 2018 | 1 |
| 2012 | 2 |
| 2004 | 1 |