Department of Cell Biology, Johns Hopkins University, Baltimore, MD, 21205, USA.
Department of Cell Biology, Johns Hopkins University, Baltimore, MD, 21205, USA; Department of Pharmacology and Molecular Science, Johns Hopkins University,Baltimore, MD, 21205, USA; Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA; Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
Semin Cell Dev Biol. 2017 Nov;71:68-74. doi: 10.1016/j.semcdb.2017.05.024. Epub 2017 Jun 1.
Metastatic cancer cells invading through dense tumor stroma experience internal and external forces that are sensed through a variety of mechanosensory proteins that drive adaptations for specific environments. Alpha-actinin-4 (ACTN4) is a member of the α-actinin family of actin crosslinking proteins that is upregulated in several types of cancers. It shares 86% protein similarity with α-actinin-1, another non-muscle ACTN isoform, which appears to have a more modest role, if any, in cancer progression. While they share regulatory mechanisms, such as phosphorylation, calcium binding, phosphatidyl inositol binding, and calpain cleavage, α-actinin-4 exhibits a unique mechanosensory regulation that α-actinin-1 does not. This behavior is mediated, at least in part, by each protein's actin-binding affinity as well as the catch-slip-bond behavior of the actin binding domains. We will discuss currently known modes of ACTN4 regulation, their interactions, and how mechanosensation may provide major therapeutic targeting potential for cancer metastasis.
转移性癌细胞穿过密集的肿瘤基质进行侵袭时，会经历各种机械感觉蛋白感知到的内外力，这些蛋白驱动适应性变化以适应特定的环境。α-辅肌动蛋白-4（ACTN4）是肌动蛋白交联蛋白 α-辅肌动蛋白家族的成员，在几种类型的癌症中上调。它与另一种非肌肉 ACTN 同工型 α-辅肌动蛋白-1 的蛋白质相似度为 86%，在癌症进展中似乎作用较小（如果有的话）。虽然它们具有相同的调节机制，如磷酸化、钙结合、磷脂酰肌醇结合和钙蛋白酶切割，但 α-辅肌动蛋白-4 表现出独特的机械感觉调节，而 α-辅肌动蛋白-1 则没有。这种行为至少部分由每种蛋白质的肌动蛋白结合亲和力以及肌动蛋白结合结构域的捕获-滑动-键行为介导。我们将讨论目前已知的 ACTN4 调节方式、它们的相互作用以及机械感觉如何为癌症转移提供主要的治疗靶向潜力。
