鼠表皮干/祖细胞的分化涉及从细胞周期中永久退出、角质化包膜的各种蛋白质和脂质成分的合成以及细胞器和细胞核的受控溶解。表皮分化失调会导致各种皮肤病的发生，包括皮肤癌。通过全基因组 shRNA 筛选，我们确定囊泡相关膜蛋白 2 (VAMP2) 是参与皮肤分化的关键因素。 VAMP2 缺失会导致体内皮肤分层和去核异常。通过定量蛋白质组学，我们进一步鉴定了一种自噬蛋白，即 200 kDa 的粘着斑激酶家族相互作用蛋白 (FIP200)，作为 VAMP2 的结合伴侣。此外，我们还发现 VAMP2 和 FIP200 对于小鼠角质形成细胞去核和表皮分化至关重要。 VAMP2 或 FIP200 的缺失会增强体内皮肤癌的发生。总之，我们的研究结果确定了表皮分化和皮肤肿瘤发生的重要分子机制。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Differentiation of murine epidermal stem/progenitor cells involves the permanent withdrawal from the cell cycle, the synthesis of various protein and lipid components for the cornified envelope, and the controlled dissolution of cellular organelles and nuclei. Deregulated epidermal differentiation contributes to the development of various skin diseases, including skin cancers. With a genome-wide shRNA screen, we identified vesicle-associated membrane protein 2 (VAMP2) as a critical factor involved in skin differentiation. Deletion of VAMP2 leads to aberrant skin stratification and enucleation in vivo. With quantitative proteomics, we further identified an autophagy protein, focal adhesion kinase family interacting protein of 200 kDa (FIP200), as a binding partner of VAMP2. Additionally, we showed that both VAMP2 and FIP200 are critical for murine keratinocyte enucleation and epidermal differentiation. Loss of VAMP2 or FIP200 enhances cutaneous carcinogenesis in vivo. Together, our findings identify important molecular mechanisms underlying epidermal differentiation and skin tumorigenesis.Copyright © 2024 Elsevier Inc. All rights reserved.