MT1-MMP regulation of matrix degradation and cell movement.

多细胞生物由数万亿个细胞组成，这些细胞通过分泌的细胞外基质（ECM）蛋白结合在一起。因此，细胞运动需要经过精心安排的努力，包括细胞通讯、重新排列，以及可能的ECM降解。细胞侵袭是一种通过组织的细胞迁移，需要降解ECM。细胞迁移通常由表面受体触发的信号级联反应和细胞形状的变化激活。细胞侵袭在成人中很少见，但在胚胎发生过程中至关重要，并在成人伤口愈合、妊娠和许多疾病中发挥关键作用，它是由24种分泌酶（称为基质金属蛋白酶（MMPs））的ECM降解所实现的。MMPs通常在迁移细胞和入侵细胞中表达。但是细胞在组织中的运动并不仅仅依赖于ECM的降解，因为抑制MMP酶活性并不总是与迁移或入侵受损有关。我们的目标是确定一个关键的膜类型MMP， MT1-MMP在协调细胞运动中所起的作用。虽然在胚胎发生过程中缺乏MMP确实会导致不适当的ECM重塑和相关的血管和骨骼缺陷，但只有缺乏MT1-MMP才是胚胎致命的。虽然大多数MMPs从细胞表面释放，但膜结合的MT1-MMP也可以将信号转导到细胞中。这一点，以及我们最近在青蛙和2D和3D细胞培养中的工作，已经证明了MT1-MMP的基本作用，我们认为这是控制细胞运动的关键。MT1-MMP;1)切割ECM， 2)调节其他MMPs的活性，3)以受体样方式结合各种分泌分子，4)激活调节基因表达和细胞形态的细胞内信号级联反应。

Multicellular organisms are composed of trillions of cells held together by secreted extracellular matrix (ECM) proteins. Cells movement thus requires an orchestrated effort that involves cell communication, re-arrangements, and possibly the degradation of the ECM. Cell invasion is a type of cell migration through tissues that requires the degradation of the ECM. Cell migration is often activated by surface receptor triggered signalling cascades and changes in cell shape. Cell invasion, which is rare in adults, but crucial during embryogenesis and plays critical roles in adult wound healing, pregnancy, and in many diseases, is enabled by ECM degradation brought about by a family of 24 secreted enzymes called matrix metalloproteinases (MMPs). MMPs are often expressed in both migrating and invading cells. But the movement of cells through tissues is not simply dependent on ECM degradation, as inhibiting MMP enzymatic activity is not always associated with impaired migration nor invasion. Our objectives are to identify the roles played by a key membrane type MMP, MT1-MMP in orchestrating the movement of cells. While lack of MMP presence during embryogenesis does results in inappropriate ECM remodelling and associated vascular and skeletal defects, only the lack of MT1-MMP is embryonic lethal. While most MMPs are released from the cell surface, membrane bound MT1-MMP can also transduce signals into the cell. This, and our more recent work in frog and with 2D and 3D cell cultures has demonstrated a fundamental role for MT1-MMP, one which we believe is key to governing cell movement. MT1-MMP can; 1) cleave the ECM, 2) regulate the activity of other MMPs, 3) binds in a receptor-like fashion to a variety of secreted molecule, 4) activate intracellular signalling cascades that regulates gene expression and cell morphology.