Abstract：
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.
摘要：
间质蛋白酶的功能障碍，一种膜锚定的蛋白酶，与皮肤癌和乳腺癌的进展密切相关。表皮生长因子（EGF）诱导的间质蛋白酶激活和癌症侵袭是已知的，但机制不明。这里,我们证明了间质蛋白酶和EGF信号在癌症促进中的囊泡运输介导的相互作用。我们发现EGF诱导间质蛋白酶与EGF受体一起经历内吞作用，其次是酸诱导的内体激活。然后，活化的间质蛋白酶在外泌体上分泌，以催化肝细胞生长因子前体（pro-HGF）裂解，导致自分泌HGF/c-Met信号传导。基质蛋白酶诱导的HGF/c-Met信号代表EGF的第二个信号波，促进癌细胞散射，迁移,和入侵。这些发现证明了囊泡运输在膜间质蛋白酶的有效激活和分泌中的作用，以及间质蛋白酶和EGF信号在癌症促进中的相互调节，提供对水泡运输的生理功能以及皮肤癌和乳腺癌的分子病理机制的见解。
