VANGL2 interacts with integrin αv to regulate matrix metalloproteinase activity and cell adhesion to the extracellular matrix.
VANGL2 interacts with integrin αv to regulate matrix metalloproteinase activity and cell adhesion to the extracellular matrix.
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DOI：
10.1016/j.yexcr.2017.10.026
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发表时间：
2017-12-15
影响因子：
3.7
通讯作者：
Jessen JR
中科院分区：
文献类型：
--
作者：
Jessen TN;Jessen JR
平面细胞极性（PCP）蛋白参与多种形态发生过程，包括胚胎细胞迁移和潜在的癌症进展。在斑马鱼原肠胚形成过程中，跨膜蛋白范样蛋白2 （VANGL2）是PCP和定向细胞迁移所必需的。这些细胞行为发生在纤维细胞外基质（ECM）的背景下。虽然人们认为与ECM的相互作用调节细胞迁移，但尚不清楚PCP蛋白如VANGL2如何影响这些事件。利用体外细胞培养模型系统，我们先前发现人类VANGL2负调控膜1型基质金属蛋白酶（MMP14）和分泌基质金属蛋白酶2 （MMP2）的激活。在这里，我们研究了VANGL2、整合素αvβ3和MMP2激活之间的功能关系。我们提供的证据表明，VANGL2调节细胞表面整合素αvβ3的表达和对纤维连接蛋白、层粘连蛋白和玻璃体连接蛋白的粘附。抑制MMP14/MMP2活性可抑制VANGL2敲除细胞的细胞粘附缺陷。此外，我们的数据表明，MMP14和整合素αv是增加VANGL2敲低细胞的蛋白质水解所必需的。最后，我们发现整合素αvβ3是一种新的VANGL2结合伙伴。总之，这些发现开始剖析VANGL2如何调节MMP活性和细胞粘附到ECM的分子基础。
Planar cell polarity (PCP) proteins are implicated in a variety of morphogenetic processes including embryonic cell migration and potentially cancer progression. During zebrafish gastrulation, the transmembrane protein Vang-like 2 (VANGL2) is required for PCP and directed cell migration. These cell behaviors occur in the context of a fibrillar extracellular matrix (ECM). While it is thought that interactions with the ECM regulate cell migration, it is unclear how PCP proteins such as VANGL2 influence these events. Using an in vitro cell culture model system, we previously showed that human VANGL2 negatively regulates membrane type-1 matrix metalloproteinase (MMP14) and activation of secreted matrix metalloproteinase 2 (MMP2). Here, we investigated the functional relationship between VANGL2, integrin αvβ3, and MMP2 activation. We provide evidence that VANGL2 regulates cell surface integrin αvβ3 expression and adhesion to fibronectin, laminin, and vitronectin. Inhibition of MMP14/MMP2 activity suppressed the cell adhesion defect in VANGL2 knockdown cells. Furthermore, our data show that MMP14 and integrin αv are required for increased proteolysis by VANGL2 knockdown cells. Lastly, we have identified integrin αvβ3 as a novel VANGL2 binding partner. Together, these findings begin to dissect the molecular underpinnings of how VANGL2 regulates MMP activity and cell adhesion to the ECM.
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影响因子：
3.8
作者：
Dyberg C;Papachristou P;Haug BH;Lagercrantz H;Kogner P;Ringstedt T;Wickström M;Johnsen JI
通讯作者：
Johnsen JI
影响因子：
3.7
作者：
Coyle, Rebecca C.;Latimer, Andrew;Jessen, Jason R.
通讯作者：
Jessen, Jason R.
影响因子：
64.5
作者：
Brooks, PC;Stromblad, S;Cheresh, DA
通讯作者：
Cheresh, DA
影响因子：
2.9
作者：
Iliescu, Alexandra;Gravel, Michel;Gros, Philippe
通讯作者：
Gros, Philippe
影响因子：
6.5
作者：
Hofmann, UB;Westphal, JR;van Muijen, GNP
通讯作者：
van Muijen, GNP