Loss of ALK4 promotes cancer progression through regulating TGF-β receptor N-glycosylation.
The transforming growth factor-β (TGF-β) pathway typically inhibits tumorigenesis but can promote metastasis during cancer progression. Activin receptor-like kinase 4 (ALK4), a type I TGF-β family receptor, is frequently downregulated or mutated in cancers, and reduced ALK4 expression correlates with poorer outcomes. However, its role and mechanism of action in cancer progression remains unclear. We demonstrate that ALK4 loss enhances anchorage-independent growth, migration, invasion, and epithelial-mesenchymal transition in vitro, as well as cancer progression in breast and pancreatic cancer models in vivo. Importantly, ALK4 loss promotes canonical TGF-β signaling by increasing TGF-β receptor N-linked glycosylation and stabilizing these receptors at the cell surface. Mechanistically, ALK4 loss upregulates β1,6 N-acetylglucosaminyltransferase V (MGAT5) and galectin-3, which binds MGAT5-modified glycoproteins to stabilize surface receptors. Consistent with prior observations that galectin-3 preferentially binds to MGAT5-modified glycoproteins to stabilize cell surface receptors like TGF-β receptors, we demonstrate that ALK4 loss enhances MGAT5-mediated glycosylation of TGF-β receptors, promoting their stabilization and signal transduction. Depleting MGAT5 or inhibiting N-glycosylation effectively suppresses ALK4-loss-induced TGF-β signaling and cancer progression.
