Valapala Mallika, Vishwanatha Jamboor K
Departments of Biomedical Sciences, Fort Worth, Texas 76107.
Departments of Biomedical Sciences, Fort Worth, Texas 76107; Molecular Biology and Immunology, Fort Worth, Texas 76107; Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, Texas 76107.
J Biol Chem. 2011 Sep 2;286(35):30911-30925. doi: 10.1074/jbc.M111.271155. Epub 2011 Jul 7.
Annexin A2 (AnxA2), a Ca(2+)-dependent phospholipid-binding protein, is known to associate with the plasma membrane and the endosomal system. Within the plasma membrane, AnxA2 associates in a Ca(2+) dependent manner with cholesterol-rich lipid raft microdomains. Here, we show that the association of AnxA2 with the lipid rafts is influenced not only by intracellular levels of Ca(2+) but also by N-terminal phosphorylation at tyrosine 23. Binding of AnxA2 to the lipid rafts is followed by the transport along the endocytic pathway to be associated with the intralumenal vesicles of the multivesicular endosomes. AnxA2-containing multivesicular endosomes fuse directly with the plasma membrane resulting in the release of the intralumenal vesicles into the extracellular environment, which facilitates the exogenous transfer of AnxA2 from one cell to another. Treatment with Ca(2+) ionophore triggers the association of AnxA2 with the specialized microdomains in the exosomal membrane that possess raft-like characteristics. Phosphorylation at Tyr-23 is also important for the localization of AnxA2 to the exosomal membranes. These results suggest that AnxA2 is trafficked from the plasma membrane rafts and is selectively incorporated into the lumenal membranes of the endosomes to escape the endosomal degradation pathway. The Ca(2+)-dependent exosomal transport constitutes a novel pathway of extracellular transport of AnxA2.
膜联蛋白A2（AnxA2）是一种依赖钙离子的磷脂结合蛋白，已知它与质膜和内体系统相关联。在质膜内，AnxA2以钙离子依赖的方式与富含胆固醇的脂筏微结构域相结合。在此，我们表明AnxA2与脂筏的结合不仅受细胞内钙离子水平的影响，还受酪氨酸23处N端磷酸化的影响。AnxA2与脂筏结合后，会沿着内吞途径运输，与多泡内体的腔内小泡相关联。含有AnxA2的多泡内体直接与质膜融合，导致腔内小泡释放到细胞外环境中，这促进了AnxA2从一个细胞向外源转移到另一个细胞。用钙离子载体处理会触发AnxA2与具有脂筏样特征的外泌体膜中的特殊微结构域相结合。酪氨酸23处的磷酸化对于AnxA2在外泌体膜中的定位也很重要。这些结果表明，AnxA2从质膜脂筏运输而来，并被选择性地整合到内体的腔膜中，以逃避内体降解途径。钙离子依赖的外泌体运输构成了AnxA2细胞外运输的一条新途径。
