The hyaluronan receptor for endocytosis mediates hyaluronan-dependent signal transduction via extracellular signal-regulated kinases
The hyaluronan receptor for endocytosis mediates hyaluronan-dependent signal transduction via extracellular signal-regulated kinases
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DOI：
10.1074/jbc.m709921200
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发表时间：
2008-05-30
影响因子：
4.8
通讯作者：
Weigel, Paul H.
中科院分区：
文献类型：
--
作者：
Kyosseva, Svetlana V.;Harris, Edward N.;Weigel, Paul H.
透明质酸（HA）内吞受体（HARE）介导HA和其他糖胺聚糖从淋巴和血液中的内吞清除。人HARE的两种亚型，315-和190-kDa，在肝、淋巴结和脾的窦状内皮细胞中高度表达; HARE也在眼、心脏、脑和肾的特化细胞中表达。在此，我们确定了HA与HARE的结合是否在稳定表达315-和190-kDa HARE或单独表达190-kDa HARE的Flp-In 293细胞中启动细胞内信号传导。HARE与细胞外信号调节激酶1和2（ERK 1/2），c-Jun N-末端蛋白激酶（JNK）和促分裂原活化蛋白激酶信号级联的p38成员共免疫沉淀。当将HA加入表达全长或190 kDa HARE的细胞中时，ERK磷酸化以剂量和时间依赖性方式增加，但仅含载体或HARE（Delta Link）构建体的细胞HA摄取大大降低（接近90%）。HA不诱导JNK或p38的磷酸化。在5 μ g/ml HA时，磷酸化ERK 1/2的最大增加发生在30分钟内，而在>20 μ g/ml HA时反应减弱。HA结合不增加HARE-ERK复合物的水平，但增加HARE磷酸化。这些发现证明了一种新的功能反应，当HARE结合HA时，其导致细胞内信号转导的重要介质ERK 1/2的激活。
The hyaluronan (HA) receptor for endocytosis (HARE) mediates the endocytotic clearance of HA and other glycosaminoglycans from lymph and blood. Two isoforms of human HARE, 315- and 190-kDa, are highly expressed in sinusoidal endothelial cells of liver, lymph node, and spleen; HARE is also in specialized cells in the eye, heart, brain, and kidney. Here we determined whether HA binding to HARE initiates intracellular signaling in Flp-In 293 cells stably expressing either the 315- and 190-kDa HARE or the 190-kDa HARE alone. HARE was co-immunoprecipitated with extracellular signal-regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal protein kinase (JNK), and p38 members of the mitogen-activated protein kinase signaling cascade. ERK phosphorylation increased in a dose- and time-dependent manner when HA was added to cells expressing full-length or 190-kDa HARE, but not cells with vector-only or a HARE(Delta Link) construct with greatly decreased (similar to 90%) HA uptake. HA did not induce phosphorylation of JNK or p38. A maximum increase in phospho-ERK1/2 occurred within 30 min at 5 mu g/ml HA, and the response was dampened at >20 mu g/ml HA. HA binding did not increase the level of HARE-ERK complexes, but did increase HARE phosphorylation. These findings demonstrate a novel functional response, when HARE binds HA, that leads to activation of ERK1/2, important mediators of intracellular signal transduction.