The molecular associations in clathrin-coated pit regulate β-arrestin-mediated MAPK signaling downstream of μ-opioid receptor

Shiraki, Atsuko; Shimizu, Satoshi

doi:10.1016/j.bbrc.2022.11.098

Cited by 6 publications

(3 citation statements)

References 46 publications

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“…Notably, β-arrestin-biased signaling has promoted cardiomyocyte contraction, probably through the regulation of myosin light chain (MLC) phosphorylation; β-arrestin-1 and 2 limited and facilitated dephosphorylation of MLC increasing and reducing contraction, respectively . Consistently, G-protein-independent signaling downstream of arrestins has been demonstrated and may involve ERK1/2 activation as well as sustained signaling from internalized receptors. ,− …”

Section: Resultsmentioning

confidence: 97%

Urotensin II Receptor Modulation with 1,3,4-Benzotriazepin-2-one Tetrapeptide Mimics

Wei,

Diarra,

Douchez

et al. 2023

J. Med. Chem.

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Urotensin II receptor (UT) modulators that differentiate the effects of the endogenous cyclic peptide ligands urotensin II (UII) and urotensin II-related peptide (URP) offer potential for dissecting their respective biological roles in disease etiology. Selective modulators of hUII and URP activities were obtained using 1,3,4-benzotriazepin-2-one mimics of a purported bioactive γ-turn conformation about the Bip-Lys-Tyr tripeptide sequence of urocontrin ([Bip4]URP). Considering an active β-turn conformer about the shared Phe-Trp-Lys-Tyr sequence of UII and URP, 8-substituted 1,3,4-benzotriazepin-2-ones were designed to mimic the Phe-Bip-Lys-Tyr tetrapeptide sequence of urocontrin, synthesized, and examined for biological activity. Subtle 5- and 8-position modifications resulted in biased signaling and selective modulation of hUII- or URP-induced vasoconstriction. For example, p-hydroxyphenethyl analogs 17b–d were strong Gα13 and βarr1 activators devoid of Gαq-mediated signaling. Tertiary amides 15d and 17d negatively modulated hUII-induced vasoconstriction without affecting URP-mediated responses. Benzotriazepinone carboxamides proved to be exceptional tools for elucidating the pharmacological complexity of UT.

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Section: Resultsmentioning

confidence: 97%

Urotensin II Receptor Modulation with 1,3,4-Benzotriazepin-2-one Tetrapeptide Mimics

Wei,

Diarra,

Douchez

et al. 2023

J. Med. Chem.

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“…The activation of MAPK by either β-Arrestin 1 or β-Arrestin 2 is commonly found in the GPCR-induced intracellular signalling pathway [32,33]. Recent reports demonstrated that β-Arrestin 2 triggers the activation of Erk1/2 pathway to promote melanoma and colorectal cancer metastasis [34,35].…”

Section: Discussionmentioning

confidence: 99%

GRK6 promotes triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis

Wang,

Lin,

Lin

et al. 2024

Preprint

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Background: Triple negative breast cancer (TNBC) belongs to the worst prognosis of breast cancer subtype probably because of distant metastasis to other organs, e.g. lungs. However, the mechanism underlying TNBC metastasis remains largely unknown. Methods: Bioinformatics analysis was conducted to evaluate the mRNA/protein expression and prognostic significance of G protein–coupled receptor kinase 6 (GRK6) in BC subtypes. RT-PCR assays were used to test the GRK6 expression in human BC tissues and cell lines. The in vitrocellular migration and in vivo lung colony-forming assays were established to estimate the metastatic potentials of TNBC cells. Western blotting was employed to examine protein phosphorylation, translocation and expression in the designed experiments. Results: Here we show that GRK6 upregulation is extensively detected in TNBC compared to normal mammary tissues and other BC subtypes and correlates with an increased risk for distant metastasis in TNBC patients. GRK6 knockdown suppressed but overexpression potentiated the cellular migration and lung colony-forming abilities of TNBC cells. Moreover, our data demonstrated that the posttranslational palmitoylation of GRK6 is extremely critical for activating b-Arrestin 2/mitogen-activated protein kinases (MAPKs)/NF-kB signaling axis and fostering the metastatic potentials of TNBC cells. Accordingly, the pharmaceutical inhibition of GRK6 kinase activity dramatically suppressed the activation of b-Arrestin 2, MAPKs and NF-kB and the cellular migration ability of highly metastatic MDA-MB231 cells. Conclusion: Our results not only provide a novel mechanism for TNBC metastasis but also offer a new therapeutic strategy to combat metastatic TNBC via targeting GRK6 activity.

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“…The activation of MAPK by either b-Arrestin 1 or b-Arrestin 2 is commonly found in the GPCR-induced intracellular signalling pathway [32,33]. Recent reports demonstrated that b-Arrestin 2 triggers the activation of Erk1/2 pathway to promote melanoma and colorectal cancer metastasis [34,35].…”

Section: Discussionmentioning

confidence: 99%

GRK6 palmitoylation dictates triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis

Wang,

Lin,

Lin

et al. 2024

Preprint

View full text Add to dashboard Cite

Background: Triple negative breast cancer (TNBC) belongs to the worst prognosis of breast cancer subtype probably because of distant metastasis to other organs, e.g. lungs. However, the mechanism underlying TNBC metastasis remains largely unknown. Methods: Bioinformatics analysis was conducted to evaluate the mRNA/protein expression and prognostic significance of G protein–coupled receptor kinase 6 (GRK6) in BC subtypes. RT-PCR assays were used to test the GRK6 expression in human BC tissues and cell lines. The in vitrocellular migration and in vivo lung colony-forming assays were established to estimate the metastatic potentials of TNBC cells. Western blotting was employed to examine protein phosphorylation, translocation and expression in the designed experiments. Results: Here we show that GRK6 upregulation is extensively detected in TNBC compared to normal mammary tissues and other BC subtypes and correlates with an increased risk for distant metastasis in TNBC patients. GRK6 knockdown suppressed but overexpression potentiated the cellular migration and lung colony-forming abilities of TNBC cells. Moreover, our data demonstrated that the posttranslational palmitoylation of GRK6 is extremely critical for activating b-Arrestin 2/mitogen-activated protein kinases (MAPKs)/NF-kB signaling axis and fostering the metastatic potentials of TNBC cells. Accordingly, the pharmaceutical inhibition of GRK6 kinase activity dramatically suppressed the activation of b-Arrestin 2, MAPKs and NF-kB and the cellular migration ability of highly metastatic MDA-MB231 cells. Sequentially blocking the b-Arrestin 2/MAPKs/NF-kB axis with their inhibitors predominantly mitigated the GRK6-promoted migration ability of poorly metastatic HCC1937 cells. Conclusion: Our results not only provide a novel mechanism for TNBC metastasis but also offer a new therapeutic strategy to combat metastatic TNBC via targeting GRK6 activity.

show abstract

The molecular associations in clathrin-coated pit regulate β-arrestin-mediated MAPK signaling downstream of μ-opioid receptor

Cited by 6 publications

References 46 publications

Urotensin II Receptor Modulation with 1,3,4-Benzotriazepin-2-one Tetrapeptide Mimics

Urotensin II Receptor Modulation with 1,3,4-Benzotriazepin-2-one Tetrapeptide Mimics

GRK6 promotes triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis

GRK6 palmitoylation dictates triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis

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