Cysteine (C)-X-C Receptor 4 Undergoes Transportin 1-Dependent Nuclear Localization and Remains Functional at the Nucleus of Metastatic Prostate Cancer Cells
被引:53
作者:
Don-Salu-Hewage, Ayesha S.
论文数: 0引用数: 0
h-index: 0
机构:
Clark Atlanta Univ, Ctr Canc Res & Therapeut Dev, Atlanta, GA 30314 USA
Clark Atlanta Univ, Dept Biol Sci, Atlanta, GA 30314 USAClark Atlanta Univ, Ctr Canc Res & Therapeut Dev, Atlanta, GA 30314 USA
Don-Salu-Hewage, Ayesha S.
[1
,2
]
Chan, Siu Yuen
论文数: 0引用数: 0
h-index: 0
机构:
Univ Hong Kong, Queen Mary Hosp, Dept Paediat & Adolescent Med, Hong Kong, Hong Kong, Peoples R ChinaClark Atlanta Univ, Ctr Canc Res & Therapeut Dev, Atlanta, GA 30314 USA
Chan, Siu Yuen
[3
]
McAndrews, Kathleen M.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Hong Kong, Queen Mary Hosp, Dept Paediat & Adolescent Med, Hong Kong, Hong Kong, Peoples R ChinaClark Atlanta Univ, Ctr Canc Res & Therapeut Dev, Atlanta, GA 30314 USA
McAndrews, Kathleen M.
[3
]
Chetram, Mahandranauth A.
论文数: 0引用数: 0
h-index: 0
机构:
Clark Atlanta Univ, Ctr Canc Res & Therapeut Dev, Atlanta, GA 30314 USA
Clark Atlanta Univ, Dept Biol Sci, Atlanta, GA 30314 USAClark Atlanta Univ, Ctr Canc Res & Therapeut Dev, Atlanta, GA 30314 USA
Chetram, Mahandranauth A.
[1
,2
]
Dawson, Michelle R.
论文数: 0引用数: 0
h-index: 0
机构:
Georgia Inst Technol, Sch Chem & Biomol Engn, Atlanta, GA 30332 USAClark Atlanta Univ, Ctr Canc Res & Therapeut Dev, Atlanta, GA 30314 USA
Dawson, Michelle R.
[4
]
Bethea, Danaya A.
论文数: 0引用数: 0
h-index: 0
机构:
Clark Atlanta Univ, Ctr Canc Res & Therapeut Dev, Atlanta, GA 30314 USAClark Atlanta Univ, Ctr Canc Res & Therapeut Dev, Atlanta, GA 30314 USA
Bethea, Danaya A.
[1
]
Hinton, Cimona V.
论文数: 0引用数: 0
h-index: 0
机构:
Clark Atlanta Univ, Ctr Canc Res & Therapeut Dev, Atlanta, GA 30314 USAClark Atlanta Univ, Ctr Canc Res & Therapeut Dev, Atlanta, GA 30314 USA
Hinton, Cimona V.
[1
]
机构:
[1] Clark Atlanta Univ, Ctr Canc Res & Therapeut Dev, Atlanta, GA 30314 USA
[2] Clark Atlanta Univ, Dept Biol Sci, Atlanta, GA 30314 USA
[3] Univ Hong Kong, Queen Mary Hosp, Dept Paediat & Adolescent Med, Hong Kong, Hong Kong, Peoples R China
[4] Georgia Inst Technol, Sch Chem & Biomol Engn, Atlanta, GA 30332 USA
The G-protein coupled receptor (GPCR), Cysteine (C)-X-C Receptor 4 (CXCR4), plays an important role in prostate cancer metastasis. CXCR4 is generally regarded as a plasma membrane receptor where it transmits signals that support transformation, progression and eventual metastasis. Due to the central role of CXCR4 in tumorigenesis, therapeutics approaches such as antagonist and monoclonal antibodies have focused on receptors that exist on the plasma membrane. An emerging concept for G-protein coupled receptors is that they may localize to and associate with the nucleus where they retain function and mediate nuclear signaling. Herein, we demonstrate that CXCR4 associated with the nucleus of malignant prostate cancer tissues. Likewise, expression of CXCR4 was detected in nuclear fractions among several prostate cancer cell lines, compared to normal prostate epithelial cells. Our studies identified a nuclear pool of CXCR4 and we defined a nuclear transport pathway for CXCR4. We reveal a putative nuclear localization sequence (NLS), 'RPRK', within CXCR4 that contributed to nuclear localization. Additionally, nuclear CXCR4 interacted with Transportin beta 1 and Transportin beta 1-binding to CXCR4 promoted its nuclear translocation. Importantly, G(alpha i) immunoprecipitation and calcium mobilization studies indicated that nuclear CXCR4 was functional and participated in G-protein signaling, revealing that the nuclear pool of CXCR4 retained function. Given the suggestion that functional, nuclear CXCR4 may be a mechanism underlying prostate cancer recurrence, increased metastatic ability and poorer prognosis after tumors have been treated with therapy that targets plasma membrane CXCR4, these studies addresses a novel mechanism of nuclear signaling for CXCR4, a novel mechanism of clinical targeting, and demonstrate an active nuclear pool that provides important new information to illuminate what has been primarily clinical reports of nuclear CXCR4.
机构:
Thomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USAThomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USA
Barker, Breann L.
Benovic, Jeffrey L.
论文数: 0引用数: 0
h-index: 0
机构:
Thomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USAThomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USA
机构:
Thomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USAThomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USA
Barker, Breann L.
Benovic, Jeffrey L.
论文数: 0引用数: 0
h-index: 0
机构:
Thomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USAThomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USA