Wnt Lipidation and Modifiers in Intestinal Carcinogenesis and Cancer

Abstract

The wingless (Wnt) signaling is suggested as a fundamental hierarchical pathway in regulation of proliferation and differentiation of cells. The Wnt ligands are small proteins of about 40 kDa essentially for regulation and initiation of the Wnt activity. They are secreted proteins requiring acylation for activity in the Wnt signaling cascade and for functional interactivity with transmembrane proteins. Dual lipidation is important for posttranslational activation of the overwhelming number of Wnt proteins and is probably involved in their spatial distribution. The intestinal mucosa, where Wnt signaling is essential in configuration and maintenance, is an established model to study Wnt proteins and their role in carcinogenesis and cancer. The intestinal crypt-villus/crypt-plateau axis, a cellular system with self-renewal, proliferation, and differentiation, is tightly coordinated by a Wnt gradient. In the review, some attention is given to Wnt3, Wnt3A, and Wnt2B as important members of the Wnt family to address the role of lipidation and modifiers of Wnt proteins in intestinal carcinogenesis. Wnt3 is an important player in establishing the Wnt gradient in intestinal crypts and is mainly produced by Paneth cells. Wnt2B is characterized as a mitochondrial protein and shuttles between mitochondria and the nucleus. Porcupine and ACSL5, a long-chain fatty acid activating enzyme, are introduced as modifiers of Wnts and as interesting strategy to targeting Wnt-driven carcinogenesis.

Keywords: Wnt; cancer; lipidation; modifier.

Figure 1

Scheme of canonical wingless (Wnt) protein signaling. (Left) In the absence of activated Wnt phosphorylation of β-catenin protein by a protein-kinase complex is found resulting in degradation of β-catenin; (Right) After coupling of activated Wnt to Fzd the protein-kinase complex is translocated and accumulation of β-catenin is found. The active β-catenin protein translocates into the nucleus and activates gene transcription via T cell factor (TCF) binding.

Figure 2

Scheme of Wnt lipidation and modifiers. The endoplasmic reticulum (ER)-associated acyltransferase porcupine is essential for Wnt lipidation with palmitoleic acid at S209 or equivalents and probably contributes to C77 palmitoylation. Porcupine is probably assisted by other acyl-CoA transferases (ACTs). Mitochondrial Wnt2B is arrested by ACSL5-dependent palmitoylation and does not further contribute to nuclear Wnt signaling.