Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-7288, USA.
Oncogene. 2010 Sep 30;29(39):5329-45. doi: 10.1038/onc.2010.307. Epub 2010 Aug 9.
Over the last decades, cancer research has focused on tumor suppressor genes and oncogenes. Genes in other cellular pathways has received less attention. Between 0.5% to 1% of the mammalian genome encodes for proteins that are tethered on the cell membrane via a glycosylphosphatidylinositol (GPI)-anchor. The GPI modification pathway is complex and not completely understood. Prion (PrP), a GPI-anchored protein, is infamous for being the only normal protein that when misfolded can cause and transmit a deadly disease. Though widely expressed and highly conserved, little is known about the functions of PrP. Pancreatic cancer and melanoma cell lines express PrP. However, in these cell lines the PrP exists as a pro-PrP as defined by retaining its GPI anchor peptide signal sequence (GPI-PSS). Unexpectedly, the GPI-PSS of PrP has a filamin A (FLNA) binding motif and binds FLNA. FLNA is a cytolinker protein, and an integrator of cell mechanics and signaling. Binding of pro-PrP to FLNA disrupts the normal FLNA functions. Although normal pancreatic ductal cells lack PrP, about 40% of patients with pancreatic ductal cell adenocarcinoma express PrP in their cancers. These patients have significantly shorter survival time compared with patients whose cancers lack PrP. Pro-PrP is also detected in melanoma in situ but is undetectable in normal melanocyte, and invasive melanoma expresses more pro-PrP. In this review, we will discuss the underlying mechanisms by which binding of pro-PrP to FLNA disrupts normal cellular physiology and contributes to tumorigenesis, and the potential mechanisms that cause the accumulation of pro-PrP in cancer cells.
在过去的几十年中，癌症研究主要集中在肿瘤抑制基因和癌基因上。其他细胞途径的基因受到的关注较少。哺乳动物基因组中约有 0.5%至 1%的基因编码通过糖基磷脂酰肌醇（GPI）锚定在细胞膜上的蛋白质。GPI 修饰途径复杂且尚未完全了解。朊病毒（PrP），一种 GPI 锚定蛋白，因其是唯一一种正常蛋白质而臭名昭著，当这种蛋白质错误折叠时，会导致并传播致命疾病。尽管 PrP 广泛表达且高度保守，但人们对其功能知之甚少。胰腺癌和黑色素瘤细胞系表达 PrP。然而，在这些细胞系中，PrP 作为前 PrP 存在，其特征是保留其 GPI 锚定肽信号序列（GPI-PSS）。出人意料的是，PrP 的 GPI-PSS 具有细丝蛋白 A（FLNA）结合基序并与 FLNA 结合。FLNA 是一种细胞连接蛋白，是细胞力学和信号转导的整合者。前 PrP 与 FLNA 的结合会破坏 FLNA 的正常功能。尽管正常的胰腺导管细胞缺乏 PrP，但大约 40%的胰腺导管细胞腺癌患者在其癌症中表达 PrP。与缺乏 PrP 的癌症患者相比，这些患者的生存时间明显缩短。前 PrP 也在原位黑色素瘤中检测到，但在正常黑素细胞中不可检测，侵袭性黑色素瘤表达更多的前 PrP。在这篇综述中，我们将讨论前 PrP 与 FLNA 结合破坏正常细胞生理学并导致肿瘤发生的潜在机制，以及导致前 PrP 在癌细胞中积累的潜在机制。
