Abstract
Despite the established role of integrin β4 (ITG β4) in breast cancer progression, the importance of endocytic recycling of ITG β4 and its regulatory mechanism are poorly understood. Here, we found that a sub-population of ITG β4 is sorted into early endosomes, recycled back to the plasma membrane, and secreted in the form of extracellular vesicles (EVs) upon EGF treatment in triple negative breast cancer (TNBC) cells. A metastasis suppressor, ARRDC3 (arrestin domain-containing 3) prevents EGF-driven endocytic recycling of ITG β4 by inducing NEDD4-dependent ubiquitination of ITG β4 and targeting endosomal ITG β4 into lysosomes. Endocytic recycling of ITG β4 is linked to sorting of ITG β4 into EVs (ITG β4+ EVs). ITG β4+ EVs are mainly detectable from supernatants of TNBC cells and their production is inhibited by ARRDC3 expression. ARRDC3 reduces the metastatic potentials of breast cancer cell-derived EVs by reducing ITG β4 levels in EVs. Overall, current studies provide novel mechanistic insights on the regulatory mechanism of ITG β4 recycling, and its importance in invasive potentials of TNBC EVs, thus providing the basis for therapeutic targeting of the ARRDC3/ITG β4 pathway in TNBC.
Highlights
The role of integrin β4 (ITG β4) in breast cancer progression has been well established, but ITG β4 plays a role in normal epithelia by increasing tissue integrity through formation of hemidesmosome [1,2,3]
A number of previous studies demonstrated the importance of endocytic recycling of integrins in their functions [7,8,9], but the mechanism that regulates integrin β4 (ITG β4) recycling and its implications in cancer biology needs to be investigated
Endosomal recycling of ITG β4 is a multi-step process that requires growth factor-mediated phosphorylation of ITG β4, hemidesmosome disassembly, endocytosis of ITG β4 into endosomes phosphorylation of ITG β4, hemidesmosome disassembly, endocytosis of ITG β4 into endosomes and endosome-mediated intracellular trafficking [5,23,30]
Summary
The role of integrin β4 (ITG β4) in breast cancer progression has been well established, but ITG β4 plays a role in normal epithelia by increasing tissue integrity through formation of hemidesmosome [1,2,3]. These bi-functional roles of ITG β4 are due to the tumor micro-environment that induces phosphorylation of key Ser residues in the connecting segment of ITG β4 and subsequent disassembly of hemidesmosomes (HDs) [4,5]. The regulatory mechanism of ITG β4 trafficking was understudied
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