Abstract
Galectin-1 (Gal-1) is a 14 kDa protein that has been well characterized for promoting cancer metastasis and tumor immune evasion. By localizing to the cancer cell surface, Gal-1 induces T cell apoptosis through binding T cell surface receptors. The transmembrane protein, Sushi Domain Containing 2 (SUSD2), has been previously shown to be required for Gal-1 surface presentation in breast cancer cells. Western immunoblot analysis revealed that SUSD2 is cleaved into two fragments. However, the significance of this cleavage for Gal-1 surface localization has not been investigated. To define the location of cleavage, a mutagenesis analysis of SUSD2 was performed. Our studies demonstrated that SUSD2 is cleaved at its glycine-aspartic acid-proline-histidine (GDPH) amino acid sequence. Generation of a noncleavable SUSD2 mutant (GDPH∆-SUSD2) showed that SUSD2 cleavage was required for SUSD2 and Gal-1 plasma membrane localization. Noncleavable cysteine mutants were also unable to present Gal-1 at the cell surface, further demonstrating that SUSD2 cleavage is required for Gal-1 surface presentation. Treatment with the serine protease inhibitor, Pefabloc SC, inhibited SUSD2 cleavage in a dose dependent manner, suggesting that SUSD2 is cleaved by a serine protease. Therefore, identification and inhibition of this protease may provide a new therapeutic tool for inhibiting SUSD2 and Gal-1′s combined tumorigenic function in breast cancer.
Highlights
Sushi Domain Containing 2 (SUSD2) has been studied in cancer, neurodevelopment, and as a marker for mesenchymal stem cells
Sushi Domain Containing 2 (SUSD2) is a type I transmembrane protein that is required for Gal-1 cell surface presentation
Our data suggests that SUSD2 cleavage is likely mediated by a serine protease
Summary
Sushi Domain Containing 2 (SUSD2) has been studied in cancer, neurodevelopment, and as a marker for mesenchymal stem cells. SUSD2 has been described as both protumor [1,2] and antitumor [3,4] depending on the type of cancer. SUSD2 has been identified as the antigen for the W5C5 antibody, which is used as a marker for the isolation of mesenchymal stem cells from human tonsil and bone marrow [6,7]. While SUSD2 has been studied in diverse biological systems, there are currently few studies on the biochemical properties of the protein. Knowledge of the structure and post-translational processing of SUSD2 may prove useful in determining the functions of the protein in association with health and disease
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