Vangl as a Master Scaffold for Wnt/Planar Cell Polarity Signaling in Development and Disease

Abstract

The establishment of polarity within tissues and dynamic cellular morphogenetic events are features common to both developing and adult tissues, and breakdown of these programs is associated with diverse human diseases. Wnt/Planar cell polarity (Wnt/PCP) signaling, a branch of non-canonical Wnt signaling, is critical to the establishment and maintenance of polarity in epithelial tissues as well as cell motility events critical to proper embryonic development. In epithelial tissues, Wnt/PCP-mediated planar polarity relies upon the asymmetric distribution of core proteins to establish polarity, but the requirement for this distribution in Wnt/PCP-mediated cell motility remains unclear. However, in both polarized tissues and migratory cells, the Wnt/PCP-specific transmembrane protein Vangl is required and appears to serve as a scaffold upon which the core pathway components as well as positive and negative regulators of Wnt/PCP signaling assemble. The current literature suggests that the multiple interaction domains of Vangl allow for the binding of diverse signaling partners for the establishment of context- and tissue-specific complexes. In this review we discuss the role of Vangl as a master scaffold for Wnt/PCP signaling in epithelial tissue polarity and cellular motility events in developing and adult tissues, and address how these programs are dysregulated in human disease.

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“…VANGLs also bind to DVL ( 19 , 20 ), and studies have shown that the interaction of de novo synthesized VANGLs with DVL promotes efficient recruitment of DVL from the endoplasmic reticulum to the plasma membrane, whereas the complex inhibits interaction of DVL with its downstream effector DAAM1 (Dishevelled-associated activator of morphogenesis 1) that promotes RHOA activation ( 21 ). At the apical plasma membrane, DVL is transferred from VANGL to FZD and thereby stimulates FZD-DVL complex formation.…”

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“…Generally speaking, epithelial cells exhibit two-way polarity: polarity along the apical-basal axis and that across the plane of the epithelial sheet. The latter is referred to as PCP, an essential property for regulating epithelial tissue integrity and its developmental process [7]. The airway epithelial surface is lined with numerous ciliated cells.…”

“…Frizzled and Dishevelled are core PCP proteins that constitute the Wnt signaling pathway. There are three main Wnt pathways: the canonical b-catenin-dependent pathway, the noncanonical Wnt/calcium pathway, and the noncanonical Wnt/PCP pathway [7,9]. The last pathway plays a critical role in PCP formation, and has been investigated in various organs and tissues, such as epithelial tissue [10], lung [9], cochlea [11,12], bile duct [13], kidney [14,15], vasculature [16], neural tube/crest [11,[17][18][19], gastrula [17], and malignant tumors [20].…”

“…Vangl and Prickle are another pair of core PCP proteins: Vangl is a four-span transmembrane protein, and Prickle is a cytoplasmic protein that binds to the intracellular domain of Vangl [7,9]. In vertebrates, each protein has two isoforms, Vangl1/2 and Prickle1/2.…”

“…These molecules are also involved in the noncanonical Wnt/PCP pathway [24]. Like the Frizzled/Dishevelled complex, the Vangl/Prickle complex is eccentrically localized on the apical surface of the epithelial cells, but on the opposite side of Frizzled/Dishevelled [7,9].…”