Abstract
LRP-1 is a large endocytic receptor mediating the clearance of various molecules from the extracellular matrix. LRP-1 was reported to control focal adhesion turnover to optimize the adhesion-deadhesion balance to support invasion. To better understand how LRP-1 coordinates cell-extracellular matrix interface, we explored its ability to regulate cell surface integrins in thyroid carcinomas. Using an antibody approach, we demonstrated that β1-integrin levels were increased at the plasma membrane under LRP1 silencing or upon RAP treatment, used as LRP-1 antagonist. Our data revealed that LRP-1 binds with both inactive and active β1-integrin conformations and identified the extracellular ligand-binding domains II or IV of LRP-1 as sufficient to bind β1-integrin. Using a recombinant β1-integrin, we demonstrated that LRP-1 acts as a regulator of β1-integrin intracellular traffic. Moreover, RAP or LRP-1 blocking antibodies decreased up to 36% the number of β1-integrin-containing endosomes. LRP-1 blockade did not significantly affect the levels of β1-integrin-containing lysosomes while decreasing localization of β1-integrin within Rab-11 positive vesicles. Overall, we identified an original molecular process in which LRP-1 acts as a main regulator of β1-integrin internalization and recycling in thyroid cancer cells.
Highlights
The low-density lipoprotein receptor-related protein-1 (LRP-1) is a large multifunctional endocytic receptor belonging to the low-density lipoprotein receptor family
We demonstrated that LRP-1 and β1-integrin closely colocalized in thyroid carcinomas, and we investigated whether LRP-1 may contribute to β1-integrin intracellular trafficking
We highlighted that the endocytic receptor LRP-1 establishes tight molecular connections with β1-integrin isoform at the cell surface of thyroid carcinoma cells
Summary
The low-density lipoprotein receptor-related protein-1 (LRP-1) is a large multifunctional endocytic receptor belonging to the low-density lipoprotein receptor family. As a consequence of its well-identified function in controlling extracellular proteolysis, LRP-1 was initially considered as preventing tumor aggressiveness [8]. This was reinforced by studies conducted in rodents or considering human samples that both further confirmed the existing correlation between low LRP-1 expression levels and poor survival [17,18,19]. Despite these experimental and clinical data, the overall contribution of LRP-1 to tumor progression appears much more complex, remaining mostly misunderstood and somehow controversial. We recently identified LRP-1 as a main endocytic receptor for the hyaluronan receptor CD44, fundamentally regulating tumor cell morphology and ECM attachment [28]
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