Maintaining the correct ratio of apical, basal, and lateral membrane domains is important for epithelial physiology. Here, we show that CD2AP is a critical determinant of epithelial membrane proportions. Depletion of CD2AP or phosphoinositide 3-kinase (PI3K) inhibition results in loss of F-actin and expansion of apical–basal domains, which comes at the expense of lateral membrane height in MDCK cells. We demonstrate that the SH3 domains of CD2AP bind to PI3K and are necessary for PI3K activity along lateral membranes and constraining cell area. Tethering the SH3 domains of CD2AP or p110γ to the membrane is sufficient to rescue CD2AP-knockdown phenotypes. CD2AP and PI3K are both upstream and downstream of actin polymerization. Since CD2AP binds to both actin filaments and PI3K, CD2AP might bridge actin assembly to PI3K activation to form a positive feedback loop to support lateral membrane extension. Our results provide insight into the squamous to cuboidal to columnar epithelial transitions seen in complex epithelial tissues in vivo.

中文翻译：

---

CD2AP 将肌动蛋白与 PI3 激酶活性联系起来，以延长上皮细胞高度并限制细胞面积

保持顶膜、基底膜和侧膜域的正确比例对于上皮生理学很重要。在这里，我们证明 CD2AP 是上皮膜比例的关键决定因素。CD2AP 或磷酸肌醇 3 激酶 (PI3K) 抑制作用的耗尽会导致 F-肌动蛋白损失和顶端-基底域扩张，这是以 MDCK 细胞侧膜高度为代价的。我们证明 CD2AP 的 SH3 结构域与 PI3K 结合，并且对于沿侧膜和限制细胞区域的 PI3K 活性是必需的。将 CD2AP 或 p110γ 的 SH3 结构域束缚在膜上足以挽救 CD2AP 敲低表型。CD2AP 和 PI3K 都是肌动蛋白聚合的上游和下游。由于 CD2AP 与肌动蛋白丝和 PI3K 结合，因此 CD2AP 可能将肌动蛋白组装与 PI3K 激活桥接起来，形成正反馈环以支持侧膜延伸。我们的结果提供了对体内复杂上皮组织中鳞状上皮到立方状上皮到柱状上皮转变的深入了解。