Jiangsu key lab of Drug Screening, Jiangsu key lab of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, China.
Research Center for High Altitude Medicine, Qing Hai University, Xining 810001, China.
Int J Biol Sci. 2018 Apr 30;14(6):654-666. doi: 10.7150/ijbs.24765. eCollection 2018.
Cell-matrix interactions play critical roles in cell adhesion, tissue remodeling and cancer metastasis. Discoidin domain receptor 2 (DDR2) is a collagen receptor belonging to receptor tyrosine kinase (RTK) family. It is a powerful regulator of collagen deposition in the extracellular matrix (ECM). Although the oligomerization of DDR extracellular domain (ECD) proteins can affect matrix remodeling by inhibiting fibrillogenesis, it is still unknown how cellular DDR2 is incorporated into collagen matrix. Using 3-dimentional (3D) imaging for migrating cells, we identified a novel mechanism that explains how DDR2 incorporating into collagen matrix, which we named as posterior remnant tethering. We followed the formation of these remnants and identified that DDR2 clusters formed at the retracting phase of a pseudopodium, then these clusters were tethered to fibrillar collagen and peeled off from the cell body to generate DDR2 containing posterior remnants. Inhibition of β1-integrin or Rac1 activity abrogated the remnant formation. Thus, our findings unveil a special cellular mechanism for DDR2 clusters incorporating into collagen matrix in an integrin-dependent manner.
细胞-基质相互作用在细胞黏附、组织重塑和癌症转移中起着关键作用。盘状结构域受体 2（DDR2）是一种胶原受体，属于受体酪氨酸激酶（RTK）家族。它是细胞外基质（ECM）中胶原沉积的有力调节剂。尽管 DDR 细胞外结构域（ECD）蛋白的寡聚化可以通过抑制原纤维形成来影响基质重塑，但仍不清楚细胞 DDR2 如何整合到胶原基质中。通过对迁移细胞的 3 维（3D）成像，我们确定了一种新的机制，解释了 DDR2 如何整合到胶原基质中，我们将其命名为后残体束缚。我们跟踪这些残余物的形成，并发现 DDR2 簇在伪足的回缩阶段形成，然后这些簇被束缚到纤维状胶原上，并从细胞体上剥离下来，形成含有 DDR2 的后残余物。抑制β1 整合素或 Rac1 活性会破坏残余物的形成。因此，我们的发现揭示了一种特殊的细胞机制，用于 DDR2 簇以整合素依赖的方式整合到胶原基质中。
