Discoidin Domain Receptor 1 Protein Is a Novel Modulator of Megakaryocyte-Collagen Interactions
Discoidin Domain Receptor 1 Protein Is a Novel Modulator of Megakaryocyte-Collagen Interactions
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DOI：
10.1074/jbc.m112.431528
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发表时间：
2013-06-07
影响因子：
4.8
通讯作者：
Balduini, Alessandra
中科院分区：
文献类型：
--
作者：
Abbonante, Vittorio;Gruppi, Cristian;Balduini, Alessandra
越来越多的证据表明，细胞外基质调节巨核细胞（MK）发育的许多方面;然而，在不同的细胞外基质受体中，整合素α 2 β 1和糖蛋白VI是血小板和MK中研究的唯一胶原受体。在这项研究中，我们证明了新的胶原蛋白受体盘状结构域受体1（DDR 1）的表达，人MK在mRNA和蛋白质水平，并提供证据的DDR 1参与调节MK运动的I型胶原蛋白通过一种机制的基础上的SHP 1磷酸酶和脾酪氨酸激酶（Syk）的活性。具体而言，我们证明了DDR 1与I型胶原蛋白结合的抑制，保留了其他胶原蛋白受体，糖蛋白VI，α 2 β 1和LAIR-1的参与，决定了MK迁移的减少，这是由于SHP 1磷酸酶活性的降低和其主要底物Syk磷酸化水平的随之增加。一致地，抑制Syk活性恢复MK在I型胶原上的迁移。总之，我们报告了一种新的胶原蛋白受体在人MK上的表达和功能，我们指出，为了更好地了解骨髓环境中MK-胶原蛋白的相互作用，需要增加复杂性。
Growing evidence demonstrates that extracellular matrices regulate many aspects of megakaryocyte (MK) development; however, among the different extracellular matrix receptors, integrin alpha 2 beta 1 and glycoprotein VI are the only collagen receptors studied in platelets and MKs. In this study, we demonstrate the expression of the novel collagen receptor discoidin domain receptor 1 (DDR1) by human MKs at both mRNA and protein levels and provide evidence of DDR1 involvement in the regulation of MK motility on type I collagen through a mechanism based on the activity of SHP1 phosphatase and spleen tyrosine kinase (Syk). Specifically, we demonstrated that inhibition of DDR1 binding to type I collagen, preserving the engagement of the other collagen receptors, glycoprotein VI, alpha 2 beta 1, and LAIR-1, determines a decrease in MK migration due to the reduction in SHP1 phosphatase activity and consequent increase in the phosphorylation level of its main substrate Syk. Consistently, inhibition of Syk activity restored MK migration on type I collagen. In conclusion, we report the expression and function of a novel collagen receptor on human MKs, and we point out that an increasing level of complexity is necessary to better understand MK-collagen interactions in the bone marrow environment.