Raymond Purves Bone and Joint Research Laboratory, Kolling Institute, Northern Sydney Local Health District, St. Leonards, NSW 2065, Australia; Graduate School of Biomedical Engineering, University of New South Wales, Sydney, NSW 2052, Australia; Sydney Medical School, Northern, The University of Sydney, Australia; Faculty of Medicine and Health, University of Sydney, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia.
Int J Biochem Cell Biol. 2020 Nov;128:105849. doi: 10.1016/j.biocel.2020.105849. Epub 2020 Sep 16.
This study reviewed some new aspects of the modular proteoglycan perlecan, a colossal proteoglycan with a 467 kDa core protein and five distinct functional domains. Perlecan is a heparan sulphate proteoglycan that transiently displays native CS sulphation motifs 4-C-3 and 7-D-4 during tissue morphogenesis these are expressed by progenitor cell populations during tissue development. Perlecan is susceptible to fragmentation by proteases during tissue development and in pathological tissues particularly in domains IV and V. The fragmentation pattern of domain IV has been suggested as a means of grading prostate cancer. Domain V of perlecan is of interest due to its interactive properties with integrin α5β1 that promotes pericyte migration enhancing PDGF-BB-induced phosphorylation of PDGFRβ, Src homology region 2 domain-containing phosphatase-2, and focal adhesion kinase supporting the repair of the blood brain barrier following ischaemic stroke. Fragments of domain V can also interact with α2β1 integrin disrupting tube formation by endothelial cells. LG1-LG2, LG3 fragments can antagonise VEGFR2, and α2β1 integrin interactions preventing angiogenesis by endothelial cells. These domain V fragments are of interest as potential anti-tumour agents. Perlecan attached to the luminal surfaces of endothelial cells in blood vessels acts as a flow sensor that signals back to endothelial and smooth muscle cells to regulate vascular tone and blood pressure. Perlecan also acts as a flow sensor in the lacuno-canalicular space regulating osteocytes and bone homeostasis. Along with its biomechanical regulatory properties in cartilaginous tissues this further extends the functional repertoire of this amazingly diverse functional proteoglycan.
本研究回顾了模块化蛋白聚糖 perlecan 的一些新方面，perlecan 是一种巨大的蛋白聚糖，其核心蛋白分子量为 467 kDa，具有五个不同的功能结构域。perlecan 是一种肝素硫酸蛋白聚糖，在组织形态发生过程中短暂地表现出天然 CS 硫酸化基序 4-C-3 和 7-D-4，这些基序在组织发育过程中由祖细胞群体表达。在组织发育和病理组织中，perlecan 容易被蛋白酶碎片化，尤其是在结构域 IV 和 V 中。结构域 IV 的碎片化模式被认为是前列腺癌分级的一种手段。perlecan 的结构域 V 因其与整合素 α5β1 的相互作用特性而受到关注，这种相互作用促进周细胞迁移，增强 PDGF-BB 诱导的 PDGFRβ、Src 同源结构域 2 富含磷酸酶-2 和粘着斑激酶的磷酸化，支持缺血性中风后血脑屏障的修复。结构域 V 的片段也可以与α2β1 整合素相互作用，破坏内皮细胞的管状形成。LG1-LG2、LG3 片段可以拮抗 VEGFR2 和α2β1 整合素相互作用，阻止内皮细胞的血管生成。这些结构域 V 片段作为潜在的抗肿瘤药物很有研究意义。perlecan 附着在血管内皮细胞的腔面表面，作为一种流动传感器，向内皮和平滑肌细胞发出信号，以调节血管张力和血压。perlecan 还作为 lacuno-canalicular 空间中的流动传感器，调节破骨细胞和骨稳态。除了在软骨组织中的生物力学调节特性外，这进一步扩展了这种惊人多样的多功能蛋白聚糖的功能范围。
