Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, USC Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90089-9176, USA.
Biochem J. 2011 Mar 1;434(2):181-8. doi: 10.1042/BJ20101569.
GRP78 (glucose-regulated protein of 78 kDa) is traditionally regarded as a major ER (endoplasmic reticulum) chaperone facilitating protein folding and assembly, protein quality control, Ca(2+) binding and regulating ER stress signalling. It is a potent anti-apoptotic protein and plays a critical role in tumour cell survival, tumour progression and angiogenesis, metastasis and resistance to therapy. Recent evidence shows that GRP78 can also exist outside the ER. The finding that GRP78 is present on the surface of cancer but not normal cells in vivo represents a paradigm shift on how GRP78 controls cell homoeostasis and provides an opportunity for cancer-specific targeting. Cell-surface GRP78 has emerged as an important regulator of tumour cell signalling and viability as it forms complexes with a rapidly expanding repertoire of cell-surface protein partners, regulating proliferation, PI3K (phosphoinositide 3-kinase)/Akt signalling and cell viability. Evidence is also emerging that GRP78 serves as a receptor for viral entry into host cells. Additionally, a novel cytosolic form of GRP78 has been discovered prominently in leukaemia cells. These, coupled with reports of nucleus- and mitochondria-localized forms of GRP78, point to the previously unanticipated role of GRP78 beyond the ER that may be critical for cell viability and therapeutic targeting.
GRP78（葡萄糖调节蛋白 78kDa）传统上被认为是内质网（ER）的主要伴侣蛋白，有助于蛋白质折叠和组装、蛋白质质量控制、Ca（2+）结合和调节 ER 应激信号。它是一种有效的抗凋亡蛋白，在肿瘤细胞存活、肿瘤进展和血管生成、转移以及对治疗的耐药性中发挥着关键作用。最近的证据表明，GRP78 也可以存在于 ER 之外。体内发现 GRP78 存在于癌细胞表面而不存在于正常细胞表面，这代表着关于 GRP78 如何控制细胞内稳态的观念发生了转变，并为癌症特异性靶向提供了机会。细胞表面 GRP78 已成为肿瘤细胞信号和活力的重要调节剂，因为它与快速扩展的细胞表面蛋白伴侣形成复合物，调节增殖、PI3K（磷酸肌醇 3-激酶）/Akt 信号和细胞活力。越来越多的证据表明，GRP78 是病毒进入宿主细胞的受体。此外，还在白血病细胞中发现了一种新型胞质形式的 GRP78。这些证据，加上细胞核和线粒体定位形式的 GRP78 的报告，表明 GRP78 在 ER 之外的作用超出了之前的预期，这对于细胞活力和治疗靶向可能至关重要。
