β-Arrestin-2 Counters CXCR7-Mediated EGFR Transactivation and Proliferation

Kallifatidis, Georgios; Muñoz, Daniel; Singh, Rajendra K.; Salazar, Nicole; Hoy, James J.; Lokeshwar, Balakrishna L.

doi:10.1158/1541-7786.mcr-15-0498

Cited by 33 publications

(30 citation statements)

References 25 publications

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“…Cell preparation and measurements were carried out as previously reported 13, 35 . Primary antibodies used for this assay are listed in Supplementary Table S2.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of androgen receptor promotes CXC-chemokine receptor 7-mediated prostate cancer cell survival

Hoy

Kallifatidis

Smith

et al. 2017

Sci Rep

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The atypical C-X-C chemokine receptor 7 (CXCR7) has been implicated in supporting aggressive cancer phenotypes in several cancers including prostate cancer. However, the mechanisms driving overexpression of this receptor in cancer are poorly understood. This study investigates the role of androgen receptor (AR) in regulating CXCR7. Androgen deprivation or AR inhibition significantly increased CXCR7 expression in androgen-responsive prostate cancer cell lines, which was accompanied by enhanced epidermal growth factor receptor (EGFR)-mediated mitogenic signaling, promoting tumor cell survival through an androgen-independent signaling program. Using multiple approaches we demonstrate that AR directly binds to the CXCR7 promoter, suppressing transcription. Clustered regularly interspaced short palindromic repeats (CRISPR) directed Cas9 nuclease-mediated gene editing of CXCR7 revealed that prostate cancer cells depend on CXCR7 for proliferation, survival and clonogenic potential. Loss of CXCR7 expression by CRISPR-Cas9 gene editing resulted in a halt of cell proliferation, severely impaired EGFR signaling and the onset of cellular senescence. Characterization of a mutated CXCR7-expressing LNCaP cell clone showed altered intracellular signaling and reduced spheroid formation potential. Our results demonstrate that CXCR7 is a potential target for adjuvant therapy in combination with androgen deprivation therapy (ADT) to prevent androgen-independent tumor cell survival.

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“…Cell preparation and measurements were carried out as previously reported 13, 35 . Primary antibodies used for this assay are listed in Supplementary Table S2.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of androgen receptor promotes CXC-chemokine receptor 7-mediated prostate cancer cell survival

Hoy

Kallifatidis

Smith

et al. 2017

Sci Rep

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“…25,29,86 β-arrestin2 inhibits EGFR transactivation by CXCR7 and counteracts mitogenic signaling and cell proliferation. 87 On the other hand, β-arrestins promote sphingosine-1-phosphate-induced transactivation of Fetal Liver Kinase 1 (Flk-1) through S1P1/S1P3 receptors, resulting in mouse embryonic stem cell proliferation. 88 β-arrestins also mediate EGFR transactivation by the β 1 AR, 89 a genetic variant of α 1 AR, 90 ET 1A R, 91 urotensin II receptor (UTR), 92 GPR39 93 and GPR54.…”

Section: β-Arrestin-dependent Signaling Via Scaffoldingmentioning

confidence: 99%

G Protein–Coupled Receptor Signaling Through β-Arrestin–Dependent Mechanisms

Jean-Charles¹,

Kaur

Shenoy³

2017

Journal of Cardiovascular Pharmacology

172

106

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β-arrestin1 (or arrestin2) and β-arrestin2 (or arrestin3) are ubiquitously expressed cytosolic adaptor proteins that were originally discovered for their inhibitory role in G protein-coupled receptor (GPCR) signaling via heterotrimeric G proteins. However, further biochemical characterization revealed that β-arrestins do not just ‘block’ the activated GPCRs, but trigger endocytosis and kinase activation leading to specific signaling pathways that can be localized on endosomes. The signaling pathways initiated by β-arrestins were also found to be independent of G protein activation by GPCRs. The discovery of ligands that blocked G protein activation but promoted β-arrestin binding, or vice-versa, suggested the exciting possibility of selectively activating intracellular signaling pathways. Additionally, it is becoming increasingly evident that β-arrestin-dependent signaling is extremely diverse and provokes distinct cellular responses through different GPCRs even when the same effector kinase is involved. In this review, we summarize various signaling pathways mediated by β-arrestins and highlight the physiologic effects of β-arrestin-dependent signaling.

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“…b-Arrestins act downstream of G-protein-coupled receptors (GPCR), which essentially regulate every physiologic process in the human body (10). We and others have demonstrated the role of b-Arrestins in progression and metastasis in several cancers (11)(12)(13). b-Arrestins are known to uncouple GPCRs from heterotrimeric G proteins and target them to clathrin-coated pits for endocytosis, thus attenuating GPCR signaling.…”

Section: Introductionmentioning

confidence: 99%

β-Arrestins Regulate Stem Cell-Like Phenotype and Response to Chemotherapy in Bladder Cancer

Kallifatidis

Smith

Morera

et al. 2019

Molecular Cancer Therapeutics

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b-Arrestins are classic attenuators of G-protein-coupled receptor signaling. However, they have multiple roles in cellular physiology, including carcinogenesis. This work shows for the first time that b-arrestins have prognostic significance for predicting metastasis and response to chemotherapy in bladder cancer. b-Arrestin-1 (ARRB1) and b-arrestin-2 (ARRB2) mRNA levels were measured by quantitative RT-PCR in two clinical specimen cohorts (n ¼ 63 and 43). The role of ARRBs in regulating a stem cell-like phenotype and response to chemotherapy treatments was investigated. The consequence of forced expression of ARRBs on tumor growth and response to Gemcitabine in vivo were investigated using bladder tumor xenografts in nude mice. ARRB1 levels were significantly elevated and ARRB2 levels downregulated in cancer tissues compared with normal tissues. In multivariate analysis only ARRB2 was an independent predictor of metastasis, diseasespecific-mortality, and failure to Gemcitabine þ Cisplatin (GþC) chemotherapy; $80% sensitivity and specificity to predict clinical outcome. ARRBs were found to regulate stem cell characteristics in bladder cancer cells. Depletion of ARRB2 resulted in increased cancer stem cell markers but ARRB2 overexpression reduced expression of stem cell markers (CD44, ALDH2, and BMI-1), and increased sensitivity toward Gemcitabine. Overexpression of ARRB2 resulted in reduced tumor growth and increased response to Gemcitabine in tumor xenografts. CRISPR-Cas9-mediated gene-knockout of ARRB1 resulted in the reversal of this aggressive phenotype. ARRBs regulate cancer stem cell-like properties in bladder cancer and are potential prognostic indicators for tumor progression and chemotherapy response.

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β-Arrestin-2 Counters CXCR7-Mediated EGFR Transactivation and Proliferation

Cited by 33 publications

References 25 publications

Inhibition of androgen receptor promotes CXC-chemokine receptor 7-mediated prostate cancer cell survival

Inhibition of androgen receptor promotes CXC-chemokine receptor 7-mediated prostate cancer cell survival

G Protein–Coupled Receptor Signaling Through β-Arrestin–Dependent Mechanisms

β-Arrestins Regulate Stem Cell-Like Phenotype and Response to Chemotherapy in Bladder Cancer

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