Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway.
Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway.
Nat Cell Biol. 2017 Dec;19(12):1412-1423. doi: 10.1038/ncb3631. Epub 2017 Oct 30.
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 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.
细胞内运输和上皮细胞极性之间相互依存的分子机制还知之甚少。在这里，我们表明，细胞内 III 类磷脂酰肌醇-3-激酶（CIII-PI3K）的失活会破坏上皮组织，CIII-PI3K 可在内体上产生磷脂酰肌醇-3-磷酸（PtdIns3P）。这是由于 Liver Kinase B1（LKB1，也称为 STK11）在细胞内体中的定位失调所致，LKB1 表现出定位失调和活性增加，同时伴随着 JNK 通路激活引起的细胞异型增生样生长和侵袭行为。CIII-PI3K 的失活与 Ras 合作，以 LKB1 依赖的方式促进体内肿瘤生长。引人注目的是，LKB1 的共耗竭可逆转这些表型并恢复上皮完整性。CIII-PI3K 的内体而非自噬功能控制极性。我们确定 CIII-PI3K 的效应物 WD 重复和 FYVE 结构域包含蛋白 2（WDFY2）是果蝇组织和人类类器官中 LKB1 的调节剂。因此，我们定义了一个由 CIII-PI3K 调节的内体信号平台，LKB1 通过该平台来指导上皮极性，而 LKB1 的失调赋予了其促进肿瘤的特性。
