Activated alpha(2)-macroglobulin induces Muller glial cell migration by regulating MT1-MMP activity through LRP1

作者：Barcelona Pablo F; Jaldin Fincati Javier R; Sanchez Maria C; Chiabrando Gustavo A^*

来源：The FASEB Journal, 2013, 27(8): 3181-3197.

DOI：10.1096/fj.12-221598

• endocytosis
• intracellular traffic
• proteases
• retina
• retinopathies

In retinal proliferative diseases, Muller glial cells (MGCs) acquire migratory abilities. However, the mechanisms that regulate this migration remain poorly understood. In addition, proliferative disorders associated with enhanced activities of matrix metalloprotease 2 (MMP-2) and MMP-9 also present increased levels of the protease inhibitor (2)-macroglobulin (M-2) and its receptor, the low-density lipoprotein receptor-related protein 1 (LRP1). In the present work, we investigated whether the protease activated form of M-2, M-2*, and LRP1 are involved with the MGC migratory process. By performing wound-scratch migration and zymography assays, we demonstrated that M-2* induced cell migration and proMMP-2 activation in the human Muller glial cell line, MIO-M1. This induction was blocked when LRP1 and MT1-MMP were knocked down with siRNA techniques. Using fluorescence microscopy and biochemical procedures, we found that M-2* induced an increase in LRP1 and MT1-MMP accumulation in early endosomes, followed by endocytic recycling and intracellular distribution of MT1-MMP toward cellular protrusions. Moreover, Rab11-dominant negative mutant abrogated MT1-MMP recycling pathway, cell migration, and proMMP-2 activation induced by M-2*. In conclusion, M-2*, through its receptor LRP1, induces cellular migration of Muller glial cells by a mechanism that involves MT1-MMP intracellular traffic to the plasma membrane by a Rab11-dependent recycling pathway.

• 出版日期2013-8