Dermatan sulphate is an activating ligand of anaplastic lymphoma kinase
Dermatan sulphate is an activating ligand of anaplastic lymphoma kinase
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硫酸皮肤素是间变性淋巴瘤激酶的激活配体
DOI：
10.1093/jb/mvab085
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Sakamoto Kazuma
中科院分区：
文献类型：
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作者：
Machino Masaaki;Gong Yuanhao;Ozaki Tomoya;Suzuki Yuji;Watanabe Eri;Imagama Shiro;Kadomatsu Kenji;Sakamoto Kazuma
间变性淋巴瘤激酶（ALK）是一种受体酪氨酸激酶（RTK），在其细胞内区域含有酪氨酸激酶结构域，在中枢和外周神经系统中均有表达。rtk在配体结合和受体聚集时被激活；然而，尽管ALK具有病理意义，特别是在恶性肿瘤中，但它仍然是一种孤儿受体。最近的生化研究表明，硫酸肝素（HS）是一种未支化的硫酸聚糖，可作为ALK的配体并激活ALK。在这里，我们发现皮肤硫酸酯（DS，硫酸软骨素B）直接与ALK和HS的细胞外n端区域相互作用。DS的四糖是必需的，足以诱导ALK在酪氨酸1604处的自磷酸化，酪氨酸1604是激活ALK的标志。有趣的是，较长的低聚糖引起ALK的激活增强，HS也是如此。我们的研究结果为甘聚糖作为信号分子提供了一个新的例子，并揭示了ALK的病理生理作用。
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that harbours a tyrosine kinase domain in its intracellular region and is expressed in both central and peripheral nervous systems. RTKs are activated upon ligand binding and receptor clustering; however, ALK remains an orphan receptor despite its pathological significance, especially in malignancy. Recent biochemical work showed that heparan sulphate (HS), an unbranched sulphated glycan, acts as a ligand for and activates ALK. Here, we show that dermatan sulphate (DS, chondroitin sulphate B) directly interacts with the extracellular N-terminal region of ALK as well as HS. The tetrasaccharide of DS was required and was sufficient for inducing autophosphorylation of ALK at tyrosine 1604, a marker for activated ALK. Interestingly, longer oligosaccharides caused enhanced activation of ALK, as was the case for HS. Our results provide a novel example of glycans as signalling molecules and shed light on the pathophysiological roles of ALK.