G Protein-coupled Receptor Kinase 2 (GRK2) Promotes Breast Tumorigenesis Through a HDAC6-Pin1 Axis

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G Protein-coupled Receptor Kinase 2 (GRK2) Promotes Breast Tumorigenesis Through a HDAC6-Pin1 Axis

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Title: G Protein-coupled Receptor Kinase 2 (GRK2) Promotes Breast Tumorigenesis Through a HDAC6-Pin1 Axis
Author: Nogués, Laura; Reglero, Clara; Rivas, Verónica; Salcedo, Alicia; Lafarga, Vanesa; Neves, Maria; Ramos, Paula; Mendiola, Marta; Berjón, Alberto; Stamatakis, Kostas; Zhou, Xiao Zhen; Lu, Kun Ping; Hardisson, David; Mayor, Federico; Penela, Petronila

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Citation: Nogués, L., C. Reglero, V. Rivas, A. Salcedo, V. Lafarga, M. Neves, P. Ramos, et al. 2016. “G Protein-coupled Receptor Kinase 2 (GRK2) Promotes Breast Tumorigenesis Through a HDAC6-Pin1 Axis.” EBioMedicine 13 (1): 132-145. doi:10.1016/j.ebiom.2016.09.030. http://dx.doi.org/10.1016/j.ebiom.2016.09.030.
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Abstract: In addition to oncogenic drivers, signaling nodes can critically modulate cancer-related cellular networks to strength tumor hallmarks. We identify G-protein-coupled receptor kinase 2 (GRK2) as a relevant player in breast cancer. GRK2 is up-regulated in breast cancer cell lines, in spontaneous tumors in mice, and in a proportion of invasive ductal carcinoma patients. Increased GRK2 functionality promotes the phosphorylation and activation of the Histone Deacetylase 6 (HDAC6) leading to de-acetylation of the Prolyl Isomerase Pin1, a central modulator of tumor progression, thereby enhancing its stability and functional interaction with key mitotic regulators. Interestingly, a correlation between GRK2 expression and Pin1 levels and de-acetylation status is detected in breast cancer patients. Activation of the HDAC6-Pin1 axis underlies the positive effects of GRK2 on promoting growth factor signaling, cellular proliferation and anchorage-independent growth in both luminal and basal breast cancer cells. Enhanced GRK2 levels promote tumor growth in mice, whereas GRK2 down-modulation sensitizes cells to therapeutic drugs and abrogates tumor formation. Our data suggest that GRK2 acts as an important onco-modulator by strengthening the functionality of key players in breast tumorigenesis such as HDAC6 and Pin1.
Published Version: doi:10.1016/j.ebiom.2016.09.030
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264252/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:31731797
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