Abstract
AbstractActivated α2-macroglobulin (α2M*) and its receptor, low-density lipoprotein receptor-related protein 1 (LRP1), have been linked to proliferative retinal diseases. In Müller glial cells (MGCs), the α2M*/LRP1 interaction induces cell signaling, cell migration, and extracellular matrix remodeling, processes closely associated with proliferative disorders. However, the mechanism whereby α2M* and LRP1 participate in the aforementioned pathologies remains incompletely elucidated. Here, we investigate whether α2M* regulates both the intracellular distribution and sorting of LRP1 to the plasma membrane (PM) and how this regulation is involved in the cell migration of MGCs. Using a human Müller glial-derived cell line, MIO-M1, we demonstrate that the α2M*/LRP1 complex is internalized and rapidly reaches early endosomes. Afterward, α2M* is routed to degradative compartments, while LRP1 is accumulated at the PM through a Rab10-dependent exocytic pathway regulated by PI3K/Akt. Interestingly, Rab10 knockdown reduces both LRP1 accumulation at the PM and cell migration of MIO-M1 cells induced by α2M*. Given the importance of MGCs in the maintenance of retinal homeostasis, unravelling this molecular mechanism can potentially provide new therapeutic targets for the treatment of proliferative retinopathies.
Publisher
Springer Science and Business Media LLC
Reference54 articles.
1. Herz, J. & Strickland, D. K. LRP: a multifunctional scavenger and signaling receptor. J Clin Invest 108, 779–784, https://doi.org/10.1172/JCI13992 (2001).
2. Chu, C. T. & Pizzo, S. V. Receptor-mediated antigen delivery into macrophages. Complexing antigen to alpha 2-macroglobulin enhances presentation to T cells. J Immunol 150, 48–58 (1993).
3. Mikhailenko, I. et al. Recognition of alpha 2-macroglobulin by the low density lipoprotein receptor-related protein requires the cooperation of two ligand binding cluster regions. J Biol Chem 276, 39484–39491, https://doi.org/10.1074/jbc.M104382200 (2001).
4. Hussain, M. M., Strickland, D. K. & Bakillah, A. The mammalian low-density lipoprotein receptor family. Annu Rev Nutr 19, 141–172, https://doi.org/10.1146/annurev.nutr.19.1.141 (1999).
5. Sivak, J. M. & Fini, M. E. MMPs in the eye: emerging roles for matrix metalloproteinases in ocular physiology. Progress in retinal and eye research 21, 1–14, doi:S1350946201000155 [pii] (2002).
Cited by
9 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献