The molecular mechanisms underlying the interdependence between intracellular trafficking and epithelial cell polarity are poorly understood. Here we show that inactivation of class III phosphatidylinositol-3-OH kinase (CIII-PI3K), which produces phosphatidylinositol-3-phosphate (PtdIns3P) on endosomes, disrupts epithelial organization. This is caused by dysregulation of endosomally localized Liver Kinase B1 (LKB1, also known as STK11), which shows delocalized and increased activity accompanied by dysplasia-like growth and invasive behaviour of cells provoked by JNK pathway activation. CIII-PI3K inactivation cooperates with Ras^V12 to promote tumour growth in vivo in an LKB1-dependent manner. Strikingly, co-depletion of LKB1 reverts these phenotypes and restores epithelial integrity. The endosomal, but not autophagic, function of CIII-PI3K controls polarity. We identify the CIII-PI3K effector, WD repeat and FYVE domain-containing 2 (WDFY2), as an LKB1 regulator in Drosophila tissues and human organoids. Thus, we define a CIII-PI3K-regulated endosomal signalling platform from which LKB1 directs epithelial polarity, the dysregulation of which endows LKB1 with tumour-promoting properties.

中文翻译：

---

III类磷脂酰肌醇-3-OH激酶通过内体LKB1调控来控制上皮的完整性。

对细胞内运输和上皮细胞极性之间相互依存的分子机制了解甚少。在这里，我们显示III类磷脂酰肌醇-3-OH激酶（CIII-PI3K）失活，这会在内体上产生磷脂酰肌醇-3-磷酸（PtdIns3P），破坏上皮组织。这是由于内体定位的肝脏激酶B1（LKB1，也称为STK11）失调引起的，该酶失活和活性增高，并伴有发育异常样生长和JNK途径激活引起的细胞侵袭行为。CIII-PI3K灭活与Ras ^V12合作以LKB1依赖性方式促进体内肿瘤生长。惊人的是，LKB1的共耗竭可恢复这些表型并恢复上皮的完整性。CIII-PI3K的内体功能而非自噬功能控制极性。我们确定CIII-PI3K效应子，WD重复和含FYVE域的2（WDFY2），作为果蝇组织和人类类器官中的LKB1调节剂。因此，我们定义了CIII-PI3K调控的内体信号传递平台，LKB1从该平台指导上皮极性，其失调赋予LKB1具有促肿瘤作用。