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

18 Citations (Scopus)

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

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Transcriptional Activation
Phosphorylation
Down-Regulation
Ligands
Chemokine Receptors
Growth
G-Protein-Coupled Receptors
RNA Interference
Epidermal Growth Factor
Small Interfering RNA
Prostate
Neoplasms
Prostatic Neoplasms
Complementary DNA
Epithelial Cells
Cell Proliferation
beta-Arrestin 1
Amphiregulin

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

β-Arrestin-2 counters CXCR7-mediated EGFR transactivation and proliferation. / Kallifatidis, Georgios; Munoz, Daniel; Singh, Rajendra Kumar; Salazar, Nicole; Hoy, James J.; Lokeshwar, Balakrishna L.

In: Molecular Cancer Research, Vol. 14, No. 5, 05.2016, p. 493-503.

Research output: Contribution to journalArticle

Kallifatidis, Georgios ; Munoz, Daniel ; Singh, Rajendra Kumar ; Salazar, Nicole ; Hoy, James J. ; Lokeshwar, Balakrishna L. / β-Arrestin-2 counters CXCR7-mediated EGFR transactivation and proliferation. In: Molecular Cancer Research. 2016 ; Vol. 14, No. 5. pp. 493-503.
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