Structural determinant of BST-2-mediated regulation of breast cancer cell motility: a role for cytoplasmic tail tyrosine residues
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Wasifa Naushad1,2,3, Wadie D. Mahauad-Fernandez1,4 and Chioma M. Okeoma1,2
1Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
2Department of Pharmacology, Stony Brook University, Stony Brook, NY, USA
3Atta-ur-Rahman School of Applied Bio sciences, National University of Sciences and Technology, Islamabad, Pakistan
4Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA, USA
Chioma M. Okeoma, email: firstname.lastname@example.org
Keywords: BST-2; tetherin; restriction factors; migration; invasion
Received: October 05, 2017 Accepted: November 09, 2017 Published: November 29, 2017
There is now irrefutable evidence that overexpression of the innate immunity protein―BST-2, in breast cancer cells is implicated in tumor growth and progression. The cellular mechanisms that control BST-2-mediated effect in tumor progression involve enhancement of cancer cell motility―migration/invasion. However, the distinct structural elements of BST-2 that mediate breast cancer cell motility remain unknown. Here, we used various motility assays and different variants of BST-2 to examine the cellular and structural mechanisms controlling BST-2-mediated cell motility. We show that BST-2 silencing in various cancer cell lines inhibits cell motility. Restoration of BST-2 expression using construct expressing wild type BST-2 rescues cell motility. Mutational analysis identifies the cytoplasmic tail of BST-2 as a novel regulator of cancer cell motility, because cell motility was significantly abrogated by substitution of the BST-2 cytoplasmic tail tyrosine residues to alanine residues. Furthermore, in a spheroid invasion model, BST-2-expressing tumor spheroids are highly invasive inside 3D Matrigel matrices. In this model, the spreading distance of BST-2-expressing spheroids was significantly higher than that of BST-2-suppressed spheroids. Collectively, our data reveal that i) BST-2-expressing breast cancer cells in spheroids are more motile than their BST-2-supressed counterparts; ii) BST-2 cytoplasmic tail regulates non-proteolytic (migration) and proteolytic (invasion) mechanisms of breast cancer cell motility; and iii) replacement of the tyrosine residues at positions 6 and 8 in the cytoplasmic tail of BST-2 with alanine residues inhibits cell motility.
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