A Mechanism Regulating G Protein-coupled Receptor Signaling That Requires Cycles of Protein Palmitoylation and Depalmitoylation

Jia, Lixia; Chisari, Mariangela; Maktabi, Mohammad H.; Sobieski, Courtney; Zhou, Hao; Konopko, Aaron M.; Martin, Brent R.; Mennerick, Steven; Blumer, Kendall J.

doi:10.1074/jbc.m113.531475

Cited by 40 publications

(31 citation statements)

References 48 publications

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“…Along the same lines, S-palmitoylation of the death receptor Fas regulates protein expression level by circumventing its degradation through the lysosomes [6]. Finally, S-palmitoylation has been reported to control G protein-coupled receptor signaling in neuronal cells [7] and to contribute to estrogen receptor alpha (ERa) signaling in organ development [8].…”

Section: S-acylationmentioning

confidence: 97%

Synthetic protein lipidation

Hannoush¹

2015

Current Opinion in Chemical Biology

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Section: S-acylationmentioning

confidence: 97%

Synthetic protein lipidation

Hannoush¹

2015

Current Opinion in Chemical Biology

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“…Dynamic cycles of palmitoylation and depalmitoylation control protein-protein interactions, protein-membrane interactions and protein stability (4–7), and complex reciprocal palmitoylation and phosphorylation events within proteins has been recognized (8, 9). Palmitoylation of intracellular proteins on cysteine residues (or more generally, protein S-fatty acylation) is carried out by members of a family of protein S-acyltransferases (PATs) that share a common motif, aspartic acid-histidine-histidine-cysteine (DHHC), with 23 family members encoded in the human genome (10, 11).…”

Section: Introductionmentioning

confidence: 99%

Systematic siRNA Screen Unmasks NSCLC Growth Dependence by Palmitoyltransferase DHHC5

Tian

Shao

et al. 2015

Molecular Cancer Research

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Protein S-palmitoylation is a widespread and dynamic post-translational modification that regulates protein-membrane interactions, protein-protein interactions, and protein stability. A large family of palmitoyl acyl transferases, termed the DHHC family due to the presence of a common catalytic motif, catalyzes S-palmitoylation; the role of these enzymes in cancer is largely unexplored. In this study, an RNAi-based screen targeting all 23 members of the DHHC family was conducted to examine the effects on the growth in non-small cell cancer (NSCLC). Interestingly, siRNAs directed against DHHC5 broadly inhibited the growth of multiple NSCLC lines but not normal human bronchial epithelial cell (HBEC) lines. Silencing of DHHC5 by lentivirus-mediated expression of DHHC5 shRNAs dramatically reduced in vitro cell proliferation, colony formation and cell invasion in a subset of cell lines that were examined in further detail. The phenotypes were restored by transfection of a wild-type DHHC5 plasmid but not by a plasmid expressing a catalytically inactive DHHC5. Tumor xenograft formation was severely inhibited by DHHC5 knockdown and rescued by DHHC5 expression, using both a conventional and tetracycline-inducible shRNA. These data indicate that DHHC5 has oncogenic capacity and contributes to tumor formation in NSCLC; thus representing a potential novel therapeutic target.

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“…Inhibition of RGS6 might be a future, multifold treatment of alcohol abuse, through control of dopaminergic signaling in the brain, with associated protection of the liver and heart [80]. R7 regulator RGS-binding protein (R7BP) is an allosteric inhibitor of R7 RGS in the brain, a process that requires palmitoylation of R7BP [81]. Palmitate turnover, which can be inhibited chemically, promotes distribution to the plasma membrane of palmitoylated R7BP, which by removing the associated RGS from the Gα protein, delays closure of G protein-regulated inwardly rectifying K + (GIRK) channels that are activated by Gi/o.…”

Section: New Pharmacological Dimensionsmentioning

confidence: 99%

New paradigms in GPCR drug discovery

Jacobson

2015

Biochemical Pharmacology

153

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G protein-coupled receptors (GPCRs) remain a major domain of pharmaceutical discovery. The discovery of GPCR lead compounds and their optimization are now structure-based, thanks to advances in X-ray crystallography, molecular modeling, protein engineering and biophysical techniques. In silico screening provides useful hit molecules. New pharmacological approaches to tuning the pleotropic action of GPCRs include: allosteric modulators, biased ligands, GPCR heterodimer-targeted compounds, manipulation of polypharmacology, receptor antibodies and tailoring of drug molecules to fit GPCR pharmacogenomics. Measurements of kinetics and drug efficacy are factors influencing clinical success. With the exception of inhibitors of GPCR kinases, targeting of intracellular GPCR signaling or receptor cycling for therapeutic purposes remains a futuristic concept. New assay approaches are more efficient and multidimensional: cell-based, label-free, fluorescence-based assays, and biosensors. Tailoring GPCR drugs to a patient’s genetic background is now being considered. Chemoinformatic tools can predict ADME-tox properties. New imaging technology visualizes drug action in vivo. Thus, there is reason to be optimistic that new technology for GPCR ligand discovery will help improve the current narrowing of the pharmaceutical pipeline.

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A Mechanism Regulating G Protein-coupled Receptor Signaling That Requires Cycles of Protein Palmitoylation and Depalmitoylation

Cited by 40 publications

References 48 publications

Synthetic protein lipidation

Synthetic protein lipidation

Systematic siRNA Screen Unmasks NSCLC Growth Dependence by Palmitoyltransferase DHHC5

New paradigms in GPCR drug discovery

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