Phosphoinositide 3-kinase p110δ promotes lumen formation through the enhancement of apico-basal polarity and basal membrane organization

Abstract

Signaling triggered by adhesion to the extracellular matrix plays a key role in the spatial orientation of epithelial polarity and formation of lumens in glandular tissues. Phosphoinositide 3-kinase signaling in particular is known to influence the polarization process during epithelial cell morphogenesis. Here, using Madin-Darby canine kidney epithelial cells grown in 3D culture, we show that the p110δ isoform of phosphoinositide 3-kinase colocalizes with focal adhesion proteins at the basal surface of polarized cells. Pharmacological, siRNA- or kinase-dead mediated inhibition of p110δ impair the early stages of lumen formation, resulting in inverted polarized cysts, with no laminin or type IV collagen assembly at cell/extracellular matrix contacts. p110δ also regulates the organization of focal adhesions and membrane localization of dystroglycan. Thus, we uncover a previously unrecognized role for p110δ in epithelial cells in the orientation of the apico-basal axis and lumen formation.

Apicobasal polarity of brain endothelial cells

“…6 At the basolateral membrane, the activity of PI3K results in the conversion of PIP2 into PIP3. 149 Like epithelial cells, endothelial cells -including cultured brain capillary endothelial cells -show an asymmetric distribution of lipids between the luminal and the abluminal membrane. 94 However, whether lipids play a role in establishing endothelial polarity is so far unknown.…”

“…6 The polar distribution of PIP2 and PIP3 is established and maintained by two enzymes, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase (PTEN) and phosphatidylinositol 3-kinase (PI3K), which localize to the apical and basolateral membrane, respectively. 6,149 At the apical membrane, PTEN catalyzes the formation of PIP2 and the removal of PIP3. 6 At the basolateral membrane, the activity of PI3K results in the conversion of PIP2 into PIP3.…”

Phosphorylation‐dependent Akt–Inversin interaction at the basal body of primary cilia

“…Recent reports suggest that PI3K p110 delta promotes lumen formation by enhancing apico‐basal polarity and basal membrane organization (Peng et al , 2015). Tubular epithelial cells are endowed with a predetermined cellular program that controls the orientation of cell division relative to the neighboring cells.…”

Molecules in medicine mini-review: isoforms of PI3K in biology and disease

“…Like wild-type p110α and p110β, p110δ may become activated by mutations in its associated p85 regulatory subunit [26]. Whereas the expression level of p110δ in leukocytes does not appear to significantly increase upon transformation, some solid tumour cell lines express high levels of the p110δ protein, where it might contribute to migration and epithelial polarity [48,39,40,49,50].…”