ß-Arrestin-2 Counters CXCR7-Mediated EGFR Transactivation and Proliferation.
Mol Cancer Res
; 14(5): 493-503, 2016 05.
Article
en En
| MEDLINE
| ID: mdl-26921391
ABSTRACT
UNLABELLED The atypical 7-transmembrane chemokine receptor, CXCR7, transactivates the EGFR leading to increased tumor growth in several tumor types. However, the molecular mechanism of CXCR7 ligand-independent EGFR transactivation is unknown. We used cDNA knock-in, RNAi and analysis of mitogenic signaling components in both normal prostate epithelial cells and prostate cancer cells to decipher the proliferation-inducing mechanism of the CXCR7-EGFR interaction. The data demonstrate that CXCR7-induced EGFR transactivation is independent of both the release of cryptic EGFR ligands (e.g., AREG/amphiregulin) and G-protein-coupled receptor signaling. An alternate signaling mechanism involving ß-arrestin-2 (ARRB2/ß-AR2) was examined by manipulating the levels of ß-AR2 and analyzing changes in LNCaP cell growth and phosphorylation of EGFR, ERK1/2, Src, and Akt. Depletion of ß-AR2 in LNCaP cells increased proliferation/colony formation and significantly increased activation of Src, phosphorylation of EGFR at Tyr-1110, and phosphorylation/activation of ERK1/2 compared with that with control shRNA. Moreover, ß-AR2 depletion downregulated the proliferation suppressor p21. Stimulation of ß-AR2-expressing cells with EGF resulted in rapid nuclear translocation of phosphorylated/activated EGFR. Downregulation of ß-AR2 enhanced this nuclear translocation. These results demonstrate that ß-AR2 is a negative regulator of CXCR7/Src/EGFR-mediated mitogenic signaling. IMPLICATIONS This study reveals that ß-AR2 functions as a tumor suppressor, underscoring its clinical importance in regulating CXCR7/EGFR-mediated tumor cell proliferation. Mol Cancer Res; 14(5); 493-503. ©2016 AACR.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Neoplasias de la Próstata
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Proteínas de Unión al GTP
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Receptores CXCR
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Receptores ErbB
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Arrestina beta 2
Límite:
Humans
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Male
Idioma:
En
Revista:
Mol Cancer Res
Asunto de la revista:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Año:
2016
Tipo del documento:
Article
País de afiliación:
Georgia