Lung Tumor Suppressor GPRC5A Binds EGFR and Restrains Its Effector Signaling.
Lung Tumor Suppressor GPRC5A Binds EGFR and Restrains Its Effector Signaling.
复制标题
DOI：
10.1158/0008-5472.can-14-2005
复制
发表时间：
2015-05
期刊：
影响因子：
11.2
通讯作者：
P. Jobling;Jay Pundavela;S. M. Oliveira;everine Roselli;Marjorie M. Walker;S. Ramachandran;Sabine Guenther
中科院分区：
文献类型：
--
作者：
P. Jobling;Jay Pundavela;S. M. Oliveira;everine Roselli;Marjorie M. Walker;S. Ramachandran;Sabine Guenther
GPRC 5A是一种G蛋白偶联受体，在肺组织中表达，但在大多数人肺癌中受到抑制。在Gprc 5a（-/-）小鼠中的研究已经确定了其在这种情况下作为肿瘤抑制功能的作用，但其作用的基础尚不清楚。在这里，我们报告GPRC 5A作为EGFR信号传导的负调节剂发挥作用。来自Gprc 5a（-/-）小鼠的小鼠气管上皮细胞（MTEC）表现出EGFR和下游STAT 3信号传导的相对增加，而GPRC 5A表达抑制EGFR和STAT 3信号传导。GPRC 5A通过其跨膜结构域与EGFR物理相互作用，这是其EGFR抑制活性所必需的。Gprc 5a（-/-）MTEC比野生型MTEC对EGFR抑制剂更敏感，表明它们依赖于EGFR信号传导来增殖和存活。在小细支气管和终末细支气管的正常上皮细胞以及Gprc 5a（-/-）小鼠肺的肿瘤中鉴定出失调的EGFR和STAT 3。此外，在这些肺中，EGFR抑制剂处理抑制EGFR和STAT 3活化沿着细胞增殖。最后，在人非小细胞肺癌细胞中异位GPRC 5A的过表达抑制EGF诱导的和组成性激活的EGFR信号传导。总之，我们的研究结果显示了GPRC 5A缺陷如何导致EGFR和STAT 3信号转导失调和肺肿瘤发生。Cancer Res; 75（9）; 1801-14.©2015 AACR.
GPRC5A is a G-protein-coupled receptor expressed in lung tissue but repressed in most human lung cancers. Studies in Gprc5a(-/-) mice have established its role as a tumor-suppressor function in this setting, but the basis for its role has been obscure. Here, we report that GPRC5A functions as a negative modulator of EGFR signaling. Mouse tracheal epithelial cells (MTEC) from Gprc5a(-/-) mice exhibited a relative increase in EGFR and downstream STAT3 signaling, whereas GPRC5A expression inhibited EGFR and STAT3 signaling. GPRC5A physically interacted with EGFR through its transmembrane domain, which was required for its EGFR inhibitory activity. Gprc5a(-/-) MTEC were much more susceptible to EGFR inhibitors than wild-type MTEC, suggesting their dependence on EGFR signaling for proliferation and survival. Dysregulated EGFR and STAT3 were identified in the normal epithelia of small and terminal bronchioles as well as tumors of Gprc5a(-/-) mouse lungs. Moreover, in these lungs EGFR inhibitor treatment inhibited EGFR and STAT3 activation along with cell proliferation. Finally, overexpression of ectopic GPRC5A in human non-small cell lung carcinoma cells inhibited both EGF-induced and constitutively activated EGFR signaling. Taken together, our results show how GPRC5A deficiency leads to dysregulated EGFR and STAT3 signaling and lung tumorigenesis. Cancer Res; 75(9); 1801-14. ©2015 AACR.