Hepatocyte polarity establishment and apical lumen formation are organized by Par3, Cdc42, and aPKC in conjunction with Lgl

Abstract

Hepatocytes differ from columnar epithelial cells by their multipolar organization, which follows the initial formation of central lumen-sharing clusters of polarized cells as observed during liver development and regeneration. The molecular mechanism for hepatocyte polarity establishment, however, has been comparatively less studied than those for other epithelial cell types. Here, we show that the tight junction protein Par3 organizes hepatocyte polarization via cooperating with the small GTPase Cdc42 to target atypical protein kinase C (aPKC) to a cortical site near the center of cell–cell contacts. In 3D Matrigel culture of human hepatocytic HepG2 cells, which mimics a process of liver development and regeneration, depletion of Par3, Cdc42, or aPKC results in an impaired establishment of apicobasolateral polarity and a loss of subsequent apical lumen formation. The aPKC activity is also required for bile canalicular (apical) elongation in mouse primary hepatocytes. The lateral membrane-associated proteins Lgl1 and Lgl2, major substrates of aPKC, seem to be dispensable for hepatocyte polarity establishment because Lgl-depleted HepG2 cells are able to form a single apical lumen in 3D culture. On the other hand, Lgl depletion leads to lateral invasion of aPKC, and overexpression of Lgl1 or Lgl2 prevents apical lumen formation, indicating that they maintain proper lateral integrity. Thus, hepatocyte polarity establishment and apical lumen formation are organized by Par3, Cdc42, and aPKC; Par3 cooperates with Cdc42 to recruit aPKC, which plays a crucial role in apical membrane development and regulation of the lateral maintainer Lgl.

Deletion of Smooth Muscle Lethal Giant Larvae 1 Promotes Neointimal Hyperplasia in Mice

“…LGL1 alters its biological activity when phosphorylated by atypical protein kinase C (aPKC) ( Graybill and Prehoda, 2014 ). Conjugated with Par/Cdc42/aPKC, LGL1 joins in the complex to regulate cell polarity and membrane development ( Plant et al, 2003 ; Tocan et al, 2021 ). In addition, LGL1 in mammals acts as a tumor suppressor in many types of cancer progression ( Tsuruga et al, 2007 ; Lu et al, 2009 ; Song et al, 2013 ; Liu et al, 2015 ).…”

Dual Function of Par3 in Tumorigenesis

“…Recently, vast studies have shown that cell polarity is related to directed migration, differentiation, proliferation, vector transportation of molecules between cell layers, and activation of immune cells, while a loss of cell polarity is correlated with the occurrence of malignant tumors (9)(10)(11)(12)(13). Partition-Defective 3 (Par3) is a PDZ-domain-containing scaffold protein that is evolutionarily conserved and essential for the establishment of the cell polarity of various cell types, such as inner ear hair cells (14), hepatocytes (15), and epithelial cells (10). In this review, we will summarize the complicated and comprehensive role of Par3 in the occurrence and development of different cancer types.…”