Department of Biomedicine, University of Bergen, Norway; Molecular Imaging Centre (MIC), University of Bergen, Norway.
Department of Biomedicine, University of Bergen, Norway; Molecular Imaging Centre (MIC), University of Bergen, Norway.
Biochim Biophys Acta Gen Subj. 2017 Nov;1861(11 Pt A):2515-2529. doi: 10.1016/j.bbagen.2017.08.024. Epub 2017 Sep 1.
Annexin A2 (AnxA2) is a multifunctional protein involved in endocytosis, exocytosis, membrane domain organisation, actin remodelling, signal transduction, protein assembly, transcription and mRNA transport, as well as DNA replication and repair.
The current knowledge of the role of phosphorylation in the functional regulation of AnxA2 is reviewed. To provide a more comprehensive treatment of this topic, we also address in depth the phosphorylation process in general and discuss its possible conformational effects. Furthermore, we discuss the apparent limitations of the methods used to investigate phosphoproteins, as exemplified by the study of AnxA2.
AnxA2 is subjected to complex regulation by post-translational modifications affecting its cellular functions, with Ser11, Ser25 and Tyr23 representing important phosphorylation sites. Thus, Ser phosphorylation of AnxA2 is involved in the recruitment and docking of secretory granules, the regulation of its association with S100A10, and sequestration of perinuclear, translationally inactive mRNP complexes. By contrast, Tyr phosphorylation of AnxA2 regulates its role in actin dynamics and increases its association with endosomal compartments. Modification of its three main phosphorylation sites is not sufficient to discriminate between its numerous functions. Thus, fine-tuning of AnxA2 function is mediated by the joint action of several post-translational modifications.
AnxA2 participates in malignant cell transformation, and its overexpression and/or phosphorylation is associated with cancer progression and metastasis. Thus, tight regulation of AnxA2 function is an integral aspect of cellular homeostasis. The presence of AnxA2 in cancer cell-derived exosomes, as well as the potential regulation of exosomal AnxA2 by phosphorylation or other PTMs, are topics of great interest.
膜联蛋白 A2（AnxA2）是一种多功能蛋白，参与胞吞作用、胞吐作用、膜域组织、肌动蛋白重塑、信号转导、蛋白质组装、转录和 mRNA 转运以及 DNA 复制和修复。
本文回顾了磷酸化在 AnxA2 功能调节中的作用的现有知识。为了更全面地处理这个主题，我们还深入探讨了磷酸化过程，并讨论了其可能的构象效应。此外，我们还讨论了用于研究磷酸化蛋白的方法所存在的明显局限性，以 AnxA2 的研究为例。
AnxA2 受到影响其细胞功能的翻译后修饰的复杂调节，Ser11、Ser25 和 Tyr23 是其重要的磷酸化位点。因此，AnxA2 的 Ser 磷酸化参与了分泌颗粒的募集和对接、其与 S100A10 相关的调节以及核周、翻译非活性 mRNP 复合物的隔离。相比之下，AnxA2 的 Tyr 磷酸化调节其在肌动蛋白动力学中的作用，并增加其与内体区室的结合。其三个主要磷酸化位点的修饰不足以区分其众多功能。因此，AnxA2 功能的精细调节是由几种翻译后修饰的共同作用介导的。
AnxA2 参与恶性细胞转化，其过表达和/或磷酸化与癌症进展和转移相关。因此，AnxA2 功能的紧密调节是细胞内稳态的一个组成部分。癌源性细胞衍生的外泌体中存在 AnxA2，以及磷酸化或其他 PTM 对外泌体 AnxA2 的潜在调节，是非常有意义的研究课题。
