Abstract
Solute carriers are increasingly recognized as participating in a plethora of pathologies, including cancer. We describe here the involvement of the orphan solute carrier Major Facilitator Superfamily Domain-containing protein 1 (MFSD1) in the regulation of tumor cell migration. Loss of MFSD1 enabled higher levels of metastasis in experimental and spontaneous metastasis mouse models. We identified an increased migratory potential in MFSD1−/− tumor cells which was mediated by increased focal adhesion turnover, reduced stability of mature inactive β1 integrin, and the resulting increased integrin activation index. We show that MFSD1 promoted recycling to the cell surface of endocytosed inactive β1 integrin and thereby protected β1 integrin from proteolytic degradation; this led to dampening of the integrin activation index. Furthermore, downregulation of MFSD1 expression was observed during the early steps of tumorigenesis, and higher MFSD1 expression levels correlate with a better cancer patient prognosis. In sum, we describe a requirement for endolysosomal MFSD1 in efficient β1 integrin recycling to suppress tumor cell dissemination.
Highlights
Solute carriers (SLCs) represent the second most numerous class of integral membrane proteins, encoded by 456 known genes [1], and are outnumbered only by G-protein-coupled receptors
We aimed to study the effect of Major Facilitator Superfamily Domain-containing protein 1 (MFSD1) on tumor cell migration
Western blotting with respective antibodies confirmed the elimination of the endogenous protein in the MFSD1−/− and Glycosylated Lysosomal Membrane Protein (GLMP)−/− lines, and we could confirm that the stability of the two proteins is mutually dependent (Supplementary Figure 1D)
Summary
Solute carriers (SLCs) represent the second most numerous class of integral membrane proteins, encoded by 456 known genes [1], and are outnumbered only by G-protein-coupled receptors. SLCs transport a broad spectrum of different molecules (e.g., sugars, neurotransmitters, vitamins, nucleosides, amino acids) and are essential for the maintenance of homeostasis in mammalian cells, tissues, and organs. About 100 SLC genes are known to cause Mendelian disorders upon mutation [2], while more are expected to have roles in multigenic diseases [1]. The interest in studying SLCs is increasing due to their roles in diverse diseases such as neurological disorders, metabolic syndrome, cardiovascular diseases, and cancer [3–6]. Only 19 SLC proteins are targeted by drugs [7], and more than 30% of SLCs remain orphans, with their physiological substrates and functions unknown [1].
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