The RSK family of kinases: emerging roles in cellular signalling.
ABSTRACT The 90 kDa ribosomal S6 kinase (RSK) family of proteins is a group of highly conserved Ser/Thr kinases that regulate diverse cellular processes, such as cell growth, cell motility, cell survival and cell proliferation. RSKs are downstream effectors of the Ras-extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signalling cascade. Significant advances in the field of RSK and ERK/MAPK signalling have occurred in the past few years, including biological insights and the discovery of novel substrates and new RSK regulatory mechanisms. Collectively, these data expand the current models of RSK signalling and highlight potential directions of research in RSK-mediated survival, growth, proliferation and migration.
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ABSTRACT: Common genetic variation and rare mutations in genes encoding calcium channel subunits have pleiotropic effects on risk for multiple neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia. To gain further mechanistic insights by extending previous gene expression data, we constructed co-expression networks in Timothy syndrome (TS), a monogenic condition with high penetrance for ASD, caused by mutations in the L-type calcium channel, Cav1.2.Genome Medicine 01/2014; 6(10):75. · 4.94 Impact Factor
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ABSTRACT: Low-density lipoprotein (LDL)-related protein-1 (LRP-1) is a member of LDL receptor family that is implicated in lipoprotein metabolism and in the homeostasis of proteases and protease inhibitors. Expression of LRP-1 is ubiquitous. Up-regulation of LRP-1 has been reported in numerous human diseases. In addition to its function as a scavenger receptor for various ligands, LRP-1 has been shown to transduce multiple intracellular signal pathways including mitogen-activated protein kinase (MAPK), Akt, Rho, and the integrin signaling. LRP-1 signaling plays an important role in the regulation of diverse cellular process, such as cell proliferation, survival, motility, differentiation, and transdifferentiation, and thus participates in the pathogenesis of organ dysfunction and injury. In this review, we focus on the current understanding of LRP-1 signaling and its roles in the development and progression of kidney disease. The role and signaling of LRP-1 in the nervous and cardiovascular systems, as well as in carcinogenesis, are also briefly discussed.International Journal of Molecular Sciences 12/2014; 15(12):22887-22901. · 2.46 Impact Factor
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ABSTRACT: The Ser/Thr protein kinase, RSK, is associated with oncogenesis, and therefore, there are ongoing efforts to develop RSK inhibitors that are suitable for use in vivo. SL0101 is a natural product that demonstrates selectivity for RSK inhibition. However, SL0101 has a short biological half-life in vivo. To address this issue we designed a set of eight cyclitol analogues, which should be resistant to acid catalyzed anomeric bond hydrolysis. The analogues were synthesized and evaluated for their ability to selectively inhibit RSK in vitro and in cell-based assays. All the analogues were prepared using a stereodivergent palladium-catalyzed glycosylation/cyclitoliza-tion for installing the aglycon. The L-cyclitol analogues were found to inhibit RSK2 in in vitro kinase activity with a similar efficacy to that of SL0101, however, the analogues were not specific for RSK in cell-based assays. In contrast, the D-isomers showed no RSK inhibitory activity in in vitro kinase assay. KEYWORDS: Ser/Thr protein kinase, cyclitol, RSK inhibition, SL0101, de novo synthesis T he Ser/Thr kinases, RSK, have emerged as a potential drug target for numerous cancers. 1 A number of RSK inhibitors have been identified 2−11 and of these the kaempferol L-rhamnoside SL0101 (1a) is the only allosteric inhibitor of RSK (Figure 1), 10 which most likely accounts for its specificity. 7 RSK is unusual in that it contains two nonidentical kinase domains. 12 On the basis of the crystal structure of SL0101 in complex with the RSK2 N-terminal kinase domain (NTKD) we generated the derivative, C3″/C4″-diacetate with a C6″-n-propyl substituent 2, which has a 50-fold higher affinity for RSK than SL0101. 13−15 In an effort to further explore the structure− activity relationship of SL0101 as it relates to RSK inhibition, we targeted for synthesis cyclitol (aka, 5a-carbasugar) analogues of SL0101 (e.g., 3 and 4, Figure 2). 16,17 We hypothesized that the cyclitol analogues (3a−c) (i.e., sans-anomeric stabilization) would serve as exact conformational mimics of the natural sugar; whereas the enantiomeric analogues (ent)-3a−c serve as control molecules. Finally, to further test the importance of the C6″ alkyl group, we envisioned preparing and evaluating the desmethyl cyclitol analogue 4.ACS Medicinal Chemistry Letters 11/2014; · 3.07 Impact Factor