Endocytic activation and exosomal secretion of matriptase stimulate the second wave of EGF signaling to promote skin and breast cancer invasion.

The dysfunction of matriptase, a membrane-anchored protease, is highly related to the progression of skin and breast cancers. Epidermal growth factor (EGF)-induced matriptase activation and cancer invasion are known but with obscure mechanisms. Here, we demonstrate a vesicular-trafficking-mediated interplay between matriptase and EGF signaling in cancer promotion. We found that EGF induces matriptase to undergo endocytosis together with the EGF receptor, followed by acid-induced activation in endosomes. Activated matriptase is then secreted extracellularly on exosomes to catalyze hepatocyte growth factor precursor (pro-HGF) cleavage, resulting in autocrine HGF/c-Met signaling. Matriptase-induced HGF/c-Met signaling represents the second signal wave of EGF, which promotes cancer cell scattering, migration, and invasion. These findings demonstrate a role of vesicular trafficking in efficient activation and secretion of membrane matriptase and a reciprocal regulation of matriptase and EGF signaling in cancer promotion, providing insights into the physiological functions of vesicular trafficking and the molecular pathological mechanisms of skin and breast cancers. [Display omitted] • EGF induces EGFR-facilitated matriptase endocytosis • Matriptase is activated by endosomal acidic conditions and secreted on exosomes • Exosomal matriptase catalyzes pro-HGF maturation to activate the HGF/c-Met pathway • Activated HGF/c-Met pathway—the second signal wave of EGF—induces cancer invasion Ye et al. show that EGF induces matriptase endocytosis together with EGFR for acidic activation in endosomes, followed by exosomal secretion. Exosomal matriptase initiates the second wave of EGF signaling via catalyzing pro-HGF maturation to activate the HGF/c-Met pathway. This vesicle-trafficking-mediated interplay between EGF and matriptase promotes SCC and TNBC invasion. [ABSTRACT FROM AUTHOR]