An annexin 2 phosphorylation switch mediates p11-dependent translocation of annexin 2 to the cell surface
An annexin 2 phosphorylation switch mediates p11-dependent translocation of annexin 2 to the cell surface
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DOI：
10.1074/jbc.m408078200
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发表时间：
2004-10-15
影响因子：
4.8
通讯作者：
Hajjar, KA
中科院分区：
文献类型：
--
作者：
Deora, AB;Kreitzer, G;Hajjar, KA
膜联蛋白2是纤溶酶原和组织纤溶酶原激活剂的前纤溶联合受体，刺激细胞表面主要的纤溶酶--纤溶酶的激活。在人类受试者中，在急性早幼粒细胞白血病中，膜联蛋白2的过度表达导致了反映细胞表面膜联蛋白2过度依赖的纤溶酶生成的出血素质(Menell，J.S.，Cesarman，G.M.，Jacovina，A.T.，McLaughlin，M.A.，Lev，E.A.，和Hajjar，K.A.(1999)N.Engl)。J.Med.340、994-1004)。此外，完全缺乏膜联蛋白2的小鼠表现出血管内纤维蛋白积累和损伤诱导的血栓清除受损(Ling Q.，Jacovina，A.T.，Deora，A.B.，Febbraio，M.，Simantov，R.，Silverstein，R.L.，Hempstead，B.L.，Mark，W.和Hajjar，K.A.(2004)J.Clin)。投资。113，38-48)。在这里，我们展示了内皮细胞膜联蛋白2，一种缺乏典型信号肽的蛋白质，在没有细胞死亡或细胞裂解的情况下，在体外和体内对短暂的温度应激做出反应，从细胞质转移到细胞质外质膜。这种受调控的反应不依赖于新的蛋白质或mRNA的合成，也不需要经典的内质网-高尔基体途径。温度应激诱导的膜联蛋白2易位依赖于蛋白p11(S100A10)的表达和膜联蛋白2的酪氨酸磷酸化，因为膜联蛋白2的释放在p11耗尽、酪氨酸激酶失活或酪氨酸23突变时完全消除。膜联蛋白2转位到细胞表面，显著增加了组织纤溶酶原激活剂依赖的纤溶酶原激活潜能，可能代表了一种新的应激诱导的蛋白质分泌途径。
Annexin 2 is a profibrinolytic co-receptor for plasminogen and tissue plasminogen activator that stimulates activation of the major fibrinolysin, plasmin, at cell surfaces. In human subjects, overexpression of annexin 2 in acute promyelocytic leukemia leads to a bleeding diathesis reflective of excessive cell surface annexin 2-dependent generation of plasmin (Menell, J. S., Cesarman, G. M., Jacovina, A. T., McLaughlin, M. A., Lev, E. A., and Hajjar, K. A. ( 1999) N. Engl. J. Med. 340, 994 - 1004). In addition, mice completely deficient in annexin 2 display fibrin accumulation within blood vessels and impaired clearance of injury-induced thrombi ( Ling Q., Jacovina, A. T., Deora, A. B., Febbraio, M., Simantov, R., Silverstein, R. L., Hempstead, B. L., Mark, W., and Hajjar, K. A. ( 2004) J. Clin. Investig. 113, 38 - 48). Here, we show that endothelial cell annexin 2, a protein that lacks a typical signal peptide, translocates from the cytoplasm to the extracytoplasmic plasma membrane in response to brief temperature stress both in vitro and in vivo in the absence of cell death or cell lysis. This regulated response is independent of new protein or mRNA synthesis and does not require the classical endoplasmic reticulum-Golgi pathway. Temperature stress-induced annexin 2 translocation is dependent on both expression of protein p11 (S100A10) and tyrosine phosphorylation of annexin 2 because annexin 2 release is completely eliminated on depletion of p11, inactivation of tyrosine kinase, or mutation of tyrosine 23. Translocation of annexin 2 to the cell surface dramatically increases tissue plasminogen activator-dependent plasminogen activation potential and may represent a novel stress-induced protein secretion pathway.