β-Arrestin-2 Counters CXCR7-Mediated EGFR Transactivation and Proliferation.
β-Arrestin-2 Counters CXCR7-Mediated EGFR Transactivation and Proliferation.
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DOI：
10.1158/1541-7786.mcr-15-0498
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发表时间：
2016-05
期刊：
影响因子：
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通讯作者：
Lokeshwar BL
中科院分区：
文献类型：
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作者：
Kallifatidis G;Munoz D;Singh RK;Salazar N;Hoy JJ;Lokeshwar BL
非典型7-跨膜趋化因子受体CXCR 7反式激活表皮生长因子受体（EGFR），导致几种肿瘤类型中的肿瘤生长增加。然而，CXCR 7配体非依赖性EGFR反式激活的分子机制尚不清楚。我们使用cDNA敲入、RNA干扰（RNAi）和分析正常前列腺上皮细胞和前列腺癌细胞中的促有丝分裂信号组分来破译CXCR 7-EGFR相互作用的增殖诱导机制。数据表明CXCR 7诱导的EGFR反式激活不依赖于隐蔽EGFR配体（例如，AREG/双调蛋白）和G蛋白偶联受体（GPCR）信号传导。通过操纵β-AR 2水平并分析LNCaP细胞生长和EGFR、ERK 1/2、Src和Akt磷酸化的变化来检查涉及β-arrestin-2（ARRB 2/β-AR 2）的替代信号传导机制。与对照shRNA相比，LNCaP细胞中β-AR 2的消耗增加了增殖/集落形成，并显著增加了Src的活化、EGFR在Tyr-1110处的磷酸化和ERK 1/2的磷酸化/活化。此外，β-AR 2缺失下调了增殖抑制因子p21。用EGF刺激表达β-AR 2的细胞导致磷酸化/活化的EGFR的快速核转位。β-AR 2的下调增强了这种核转位。这些结果表明，β-AR 2是CXCR 7/Src/EGFR介导的促有丝分裂信号的负调节因子。这项研究揭示了β-AR 2作为肿瘤抑制因子的功能，强调了其在调节CXCR 7/EGFR介导的肿瘤细胞增殖中的临床重要性。
The atypical 7-transmebrane chemokine receptor, CXCR7 transactivates the epidermal growth factor receptor (EGFR) leading to increased tumor growth in several tumor types. However, the molecular mechanism of CXCR7-ligand independent EGFR-trans-activation is unknown. We used cDNA knock-in, RNA interference (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 (GPCR) 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 to 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.