4.7 Article

Activated α2-macroglobulin induces Muller glial cell migration by regulating MT1-MMP activity through LRP1

Journal

FASEB JOURNAL
Volume 27, Issue 8, Pages 3181-3197

Publisher

FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.12-221598

Keywords

endocytosis; intracellular traffic; proteases; retina; retinopathies

Funding

  1. Secretaria de Ciencia y Tecnologia de la Universidad Nacional de Cordoba (SECyTUNC) [214/10, 26/1169/08]
  2. Fondo para la Investigacion Cientifica y Tecnologica (FONCyT): Prestamo BID Proyecto de Investigacion en Ciencia y Tecnolog a (PICT) [06-01207]
  3. Proyecto de Investigacion en Ciencia y Tecnolog a Orientados (PICTO)-Glaxo [2012-0084]
  4. Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET) Proyecto de Investigacion Plurianual (PIP) [112-200801-02067]

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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.

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