TY - JOUR
T1 - β-Arrestin-2 counters CXCR7-mediated EGFR transactivation and proliferation
AU - Kallifatidis, Georgios
AU - Munoz, Daniel
AU - Singh, Rajendra Kumar
AU - Salazar, Nicole
AU - Hoy, James J.
AU - Lokeshwar, Balakrishna L
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/5
Y1 - 2016/5
N2 - 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.
AB - 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.
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U2 - 10.1158/1541-7786.MCR-15-0498
DO - 10.1158/1541-7786.MCR-15-0498
M3 - Article
C2 - 26921391
AN - SCOPUS:84969130046
SN - 1541-7786
VL - 14
SP - 493
EP - 503
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 5
ER -