Cellular uptake of proMMP-2:TIMP-2 complexes by the endocytic receptor megalin/LRP-2.

Johanns, Manuel;Lemoine, Pascale;Janssens, Virginie;Grieco, Giuseppina;Henriet, Patrick;et.al.
(2017) Scientific Reports — Vol. 7, n° 1, p. 4328 [1-8] (2017)

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Abstract
Matrix metalloproteinases (MMPs) are regulated at multiple transcriptional and post-transcriptional levels, among which receptor-mediated endocytic clearance. We previously showed that low-density lipoprotein receptor-related protein-1 (LRP-1) mediates the clearance of a complex between the zymogen form of MMP-2 (proMMP-2) and tissue inhibitor of metalloproteinases, TIMP-2, in HT1080 human fibrosarcoma cells. Here we show that, in BN16 rat yolk sac cells, proMMP-2:TIMP-2 complex is endocytosed through a distinct LRP member, megalin/LRP-2. Addition of receptor-associated protein (RAP), a natural LRP antagonist, caused accumulation of endogenous proMMP-2 and TIMP-2 in conditioned media. Incubation with RAP also inhibited membrane binding and cellular uptake of exogenous iodinated proMMP-2:TIMP-2. Moreover, antibodies against megalin/LRP-2, but not against LRP-1, inhibited binding of proMMP-2:TIMP-2 to BN16 cell surface. BIAcore analysis confirmed direct interaction between the complex and megalin/LRP-2. Conditional renal invalidation of megalin/LRP-2 in mice resulted in accumulation of proMMP-2 and TIMP-2 in their urine, highlighting the physiological relevance of the binding. We conclude that megalin/LRP-2 can efficiently mediate cell-surface binding and endocytosis of proMMP-2:TIMP-2 complex. Therefore megalin/LRP-2 can be considered as a new actor in regulation of MMP-2 activity, an enzyme crucially involved in many pathological processes.
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Johanns, M., Lemoine, P., Janssens, V., Grieco, G., Moestrup, S. K., Nielsen, R., Christensen, E. I., Courtoy, P., Emonard, H., Marbaix, E., & Henriet, P. (2017). Cellular uptake of proMMP-2:TIMP-2 complexes by the endocytic receptor megalin/LRP-2. Scientific Reports, 7(1), 4328 [1-8]. https://doi.org/10.1038/s41598-017-04648-y (Original work published 2017)