A Screen for PKN3 Substrates Reveals an Activating Phosphorylation of ARHGAP18

Dibus, Michal; Brábek, Jan; Rösel, Daniel

doi:10.3390/ijms21207769

Cited by 4 publications

(3 citation statements)

References 47 publications

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“…Nonetheless, a striking observation emerges: based on the number of participants in a feedback loop and the number of levels at which feedback acts, feedback itself is a fundamental outcome of the Rho GTPase signalling. That is, not only do the GEFs alluded to above in fact act as effectors in direct feedback, all of the major classes of effectors also participate in feedback including formins 95 , N-WASP 84 , p21-activated kinases (Paks) 97,109 , Rho kinase (ROCK) 108 , and Protein Kinase N (PKN) 107 . With respect to downstream targets, in addition to F-actin, monomeric actin (G-actin) participates in feedback 110 , as does myosin-2 106 , and Phosphatidylinositol (3,4,5)-trisphosphate (PIP3) 106,110,115 is a downstream target of Rac and CDC42 115,116 .…”

Section: [H1] Rho Gtpase Zones and Rho Gtpase Fluxmentioning

confidence: 99%

Patterning of the cell cortex by Rho GTPases

Bement,

Goryachev,

Miller

et al. 2024

Nat Rev Mol Cell Biol

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The Rho GTPases-Rho, Rac and CDC42-are small GTP-binding proteins that regulate basic biological processes such as cell locomotion, cell division and morphogenesis by promoting cytoskeleton-based changes in the cell cortex. This regulation results from active (GTP-bound) Rho GTPases stimulating target proteins that in turn promote actin assembly and myosin-2-based contraction to pattern the organization of the cortex. This basic regulatory scheme, well-supported by in vitro studies, led to the natural assumption that Rho GTPases function in vivo in an essentially linear matter, with a given process being initiated by GTPase activation and terminated by GTPase inactivation. However, a growing body of evidence based on live cell imaging, modelling, and experimental manipulation indicates that Rho GTPase activation and inactivation are often tightly coupled in space and time via signalling circuits and networks based on positive and negative feedback. In this Review, we present and discuss this evidence, and we address one of the fundamental consequences of coupled activation and inactivation: the ability of the Rho GTPases to self-organize. We discuss how Rho GTPase self-organization results in the formation of diverse spatio-temporal cortical patterns such as static clusters, oscillatory pulses, traveling wave trains, and ring-like waves. Finally, we discuss the advantages of Rho GTPase self-organization and pattern formation for cell function.

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Section: [H1] Rho Gtpase Zones and Rho Gtpase Fluxmentioning

confidence: 99%

Patterning of the cell cortex by Rho GTPases

Bement,

Goryachev,

Miller

et al. 2024

Nat Rev Mol Cell Biol

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“…The serine/threonine kinase PKN3 is an understudied kinase whose molecular function and downstream targets are largely unknown 46 . In recent studies, PKN3 has been functionally linked to metastasis, invasion and tumor growth making it a potential target for drug discovery in oncolgy 47 , 48 .…”

Section: Resultsmentioning

confidence: 99%

Chemical proteomics reveals the target landscape of 1,000 kinase inhibitors

Reinecke,

Brear,

Vornholz

et al. 2023

Nat Chem Biol

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Medicinal chemistry has discovered thousands of potent protein and lipid kinase inhibitors. These may be developed into therapeutic drugs or chemical probes to study kinase biology. Because of polypharmacology, a large part of the human kinome currently lacks selective chemical probes. To discover such probes, we profiled 1,183 compounds from drug discovery projects in lysates of cancer cell lines using Kinobeads. The resulting 500,000 compound–target interactions are available in ProteomicsDB and we exemplify how this molecular resource may be used. For instance, the data revealed several hundred reasonably selective compounds for 72 kinases. Cellular assays validated GSK986310C as a candidate SYK (spleen tyrosine kinase) probe and X-ray crystallography uncovered the structural basis for the observed selectivity of the CK2 inhibitor GW869516X. Compounds targeting PKN3 were discovered and phosphoproteomics identified substrates that indicate target engagement in cells. We anticipate that this molecular resource will aid research in drug discovery and chemical biology.

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“…In the fourth research article, Dibus et al presented data from the screening of substrates of protein kinase N3 (PKN3), a serine/threonine kinase, implicated in the tumor progression of multiple cancer variations. The authors identified a new set of potential PKN3 substrates and revealed a new negative feedback regulatory mechanism of Rho signaling, mediated by PKN3-induced ARHGAP18 activation [ 11 ]. The last research article, by Heintze et al, presents the development of diazocine-functionalized derivatives of the VEGFR-2 inhibitor axitinib, as reversibly photoswitchable inhibitors that exhibit a greater than 40-fold difference in biological activities upon irradiation [ 12 ].…”

mentioning

confidence: 99%