β-Arrestin-2 counters CXCR7-mediated EGFR transactivation and proliferation

Georgios Kallifatidis, Daniel Munoz, Rajendra Kumar Singh, Nicole Salazar, James J. Hoy, Balakrishna L Lokeshwar

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

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 b-Arrestin-2 (ARRB2/ β-AR2) was examined by manipulating the levels of β-AR2 and analyzing changes in LNCaP cell growth and phosphorylation of EGFR, ERK1/2, Src, and Akt. Depletion of β-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, β-AR2 depletion downregulated the proliferation suppressor p21. Stimulation of β-AR2-expressing cells with EGF resulted in rapid nuclear translocation of phosphorylated/activated EGFR. Downregulation of β-AR2 enhanced this nuclear translocation. These results demonstrate that β-AR2 is a negative regulator of CXCR7/Src/ EGFR-mediated mitogenic signaling.

Original languageEnglish (US)
Pages (from-to)493-503
Number of pages11
JournalMolecular Cancer Research
Volume14
Issue number5
DOIs
StatePublished - May 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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