title: β-Arrestin-2 Counters CXCR7-Mediated EGFR Transactivation and Proliferation.
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 β-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.
  
  
  
  This study reveals that β-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.
authors.affiliation: GRU Cancer Center, Augusta University (formerly Georgia Regents University), Augusta, Georgia.
authors.forename: Georgios
authors.initials: G
authors.lastname: Kallifatidis
authors.affiliation: VA Medical Center, Research Service, Miami, Florida.
authors.forename: Daniel
authors.initials: D
authors.lastname: Munoz
authors.affiliation: Department of Health and Environmental Sciences, Dow-Corning, Inc., Midland, MI.
authors.forename: Rajendra Kumar
authors.initials: RK
authors.lastname: Singh
authors.affiliation: Palo Alto VA Medical Center, Palo Alto, CA. Stanford University School of Medicine, Palo Alto, CA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Salazar
authors.affiliation: Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami-Miller School of Medicine, Miami, Florida.
authors.forename: James J
authors.initials: JJ
authors.lastname: Hoy
authors.affiliation: GRU Cancer Center, Augusta University (formerly Georgia Regents University), Augusta, Georgia. Research Service, Charlie Norwood VA Medical Center, Augusta, Georgia. blokeshwar@augusta.edu.
authors.forename: Bal L
authors.initials: BL
authors.lastname: Lokeshwar
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D006801:Humans; D008297:Male; D009154:Mutation; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism*; D034622:RNA Interference; D054387:Receptors, CXCR / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000071560:beta-Arrestin 2 / Q000235:genetics* / Q000378:metabolism
chemical_list: C501896:ACKR3 protein, human; C000605254:ARRB2 protein, human; D054387:Receptors, CXCR; D000071560:beta-Arrestin 2; C512478:EGFR protein, human; D066246:ErbB Receptors; D019204:GTP-Binding Proteins