Beyond the endoplasmic reticulum: atypical GRP78 in cell viability, signalling and therapeutic targeting.
Beyond the endoplasmic reticulum: atypical GRP78 in cell viability, signalling and therapeutic targeting.
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DOI：
10.1042/bj20101569
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发表时间：
2011-03-01
期刊：
影响因子：
--
通讯作者：
Lee AS
中科院分区：
文献类型：
--
作者：
Ni M;Zhang Y;Lee AS
GRP 78是内质网（endoplasmic reticulum，ER）的重要分子伴侣，它促进蛋白质的折叠和组装、蛋白质的质量控制、Ca 2+结合以及调节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、转移和对治疗的抵抗中起关键作用。最近的证据表明，GRP 78也可以存在于ER之外。GRP 78存在于癌症表面而不是体内正常细胞表面的发现代表了GRP 78如何控制细胞稳态的范式转变，并为癌症特异性靶向提供了机会。细胞表面GRP 78已经成为肿瘤细胞信号传导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库形成复合物，调节增殖、PI 3 K/AKT信号传导和细胞活力。也有证据表明GRP 78作为病毒进入宿主细胞的受体。此外，在白血病细胞中发现了一种新的胞质形式的GRP 78。这些，再加上GRP 78中的核和线粒体定位形式的报道，指出GRP 78在ER之外的先前未预料到的作用，这可能对细胞活力和治疗靶向至关重要。
GRP78 is traditionally regarded as a major endoplasmic reticulum (ER) chaperone facilitating protein folding and assembly, protein quality control, Ca2+ binding and regulating ER stress signaling. It is a potent anti-apoptotic protein and plays a critical role in tumor cell survival, tumor 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 homeostasis and provides an opportunity for cancer specific targeting. Cell surface GRP78 has emerged as an important regulator of tumor cell signaling and viability as it forms complexes with a rapidly expanding repertoire of cell surface protein partners, regulating proliferation, PI3K/AKT signaling 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 is discovered prominently in leukemia cells. These, coupled with report of nuclear and mitochondria localized form in GRP78, point to the previously unanticipated role of GRP78 beyond the ER that may be critical for cell viability and therapeutic targeting.