β-parvin inhibits integrin-linked kinase signaling and is downregulated in breast cancer
β-parvin inhibits integrin-linked kinase signaling and is downregulated in breast cancer
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DOI：
10.1038/sj.onc.1208112
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发表时间：
2004-11-25
期刊：
影响因子：
8
通讯作者：
Hannigan, GE
中科院分区：
文献类型：
--
作者：
Mongroo, PS;Johnstone, CN;Hannigan, GE
我们分析了乳腺肿瘤和乳腺癌细胞系的β-小腺病毒蛋白（ParvB）的表达，ParvB是一种与整合素连接激酶（ILK）结合的衔接蛋白。定量RT-PCR表明，ParvB mRNA下调，至少60%，在四个9乳腺肿瘤，相对于患者匹配的正常乳腺组织。我们还发现，相对于匹配的正常乳腺组织，在7个晚期肿瘤中的5个中，ParvB蛋白水平降低大于或等于90%。相反，ILK蛋白和激酶活性水平在这些肿瘤中升高，表明ParvB的下调刺激ILK信号传导。Western印迹分析表明，在MDA-MB-231和MCF 7乳腺癌细胞中ParvB蛋白的水平非常低，促进了ParvB对ILK信号传导的作用的功能研究。ParvB在MDA-MB-231和MCF 7细胞中的表达增加了细胞与胶原的粘附。ParvB抑制ILK激酶活性，锚定非依赖性细胞生长和MDA-MB-231细胞的体外基质胶侵袭。EGF诱导的两个ILK靶点PKB（Ser 473）和糖原合成酶激酶3 β（Ser 9）的磷酸化也被ParvB抑制。这些结果表明，ParvB抑制受体酪氨酸激酶下游的ILK信号传导。我们的研究结果表明，ParvB表达的损失是一种新的机制上调ILK活性的肿瘤。
We analysed breast tumors and breast cancer cell lines for the expression of beta-parvin (ParvB), an adaptor protein that binds to the integrin-linked kinase (ILK). Quantitative RT-PCR indicated that ParvB mRNA was downregulated, by at least 60%, in four of nine breast tumors, relative to patient-matched normal mammary gland tissue. We also found that ParvB protein levels were reduced by greater than or equal to90% in five of seven advanced tumors, relative to matched normal breast tissue. Conversely, ILK protein and kinase activity levels were elevated in these tumors, suggesting that downregulation of ParvB stimulates ILK signaling. Western blot analyses indicated very low levels of ParvB protein in MDA-MB-231 and MCF7 breast cancer cells, facilitating functional studies of the effects of ParvB on ILK signaling. Expression of ParvB in MDA-MB-231 and MCF7 cells increased cell adhesion to collagen. ParvB inhibited ILK kinase activity, anchorage-independent cell growth and in vitro matrigel invasion by MDA-MB-231 cells. EGF-induced phosphorylation of two ILK targets, PKB (Ser473) and glycogen synthase kinase 3beta (Ser9), was also inhibited by ParvB. These results indicated that ParvB inhibits ILK signaling downstream of receptor tyrosine kinases. Our results suggest that loss of ParvB expression is a novel mechanism for upregulating ILK activity in tumors.