Wnt Signaling at the Plasma Membrane: Activation, Regulation and Disease Connection

Editorial

25 October 2021

Editorial: Wnt Signaling at the Plasma Membrane: Activation, Regulation and Disease Connection

Gunes Ozhan

1,132 views

3 citations

Editors

Gunes Ozhan

Izmir Institute of Technology

Erdinc Sezgin

Karolinska Institutet (KI)

Anming Meng

Tsinghua University

Impact

Role of LRP6 as a regulator of other signaling. (A) LRP6 as a regulator of GPCR signaling. In the basal state, LRP6 interacts with G protein Gαs. In the presence of the GPCR ligand PTH, a LRP6-PTH-PTH1R ternary complex is formed, which promotes aggregation of LRP6 and membrane localization of Gαs. Production of cAMP is also upregulated in a Gαs-AC-dependent manner. cAMP activates PKA, which promotes phosphorylation of LRP6 and CREB, two well-known downstream targets of PKA. (B) LRP6 as a regulator of non-canonical Wnt signaling. Wnt5a interacts with ROR1/2 and FZD, resulting in activation of Rac, a non-canonical Wnt signaling target. Wnt5a can also interact with LRP6. In these conditions, the binding affinity of ROR1/2 and FZD to Wnt5a is reduced. As a result, Rac becomes inactive and non-canonical Wnt signaling is inhibited. Because LRP6-Wnt5a binding weakens LRP6-Wnt3a interaction, Wnt/β-catenin signaling is also inhibited. (C) LRP6 as a regulator of Hippo signaling. In a nutrient rich state, LRP6 is O-GlcNAcylated and interacts with Merlin. In this condition, activity of LATS1/2 is maintained at low levels, resulting in stabilization and activation of YAP. In nutrient starvation conditions, O-GlcNAcylation and protein levels of LRP6 are both downregulated, and Merlin changes its binding partner from LRP6 to LATS1/2, resulting in activation of LATS1/2. YAP is phosphorylated by LATS1/2 and becomes inactive. (D) LRP6 as a regulator of Wnt/STOP signaling. In G1/S phase, cyclin Y protein levels are less abundant and the phosphorylation state of LRP6 is low, resulting in higher GSK3 activity. GSK3-target proteins are thus phosphorylated and targeted for proteasomal degradation. In G2/M phase, cyclin Y protein levels peak and promote LRP6 phosphorylation, resulting in inactivation of GSK3 and stabilization of GSK3-target proteins.

Review

13 September 2021

Regulation of the Low-Density Lipoprotein Receptor-Related Protein LRP6 and Its Association With Disease: Wnt/β-Catenin Signaling and Beyond

Wonyoung Jeong

and

Eek-hoon Jho

8,906 views

38 citations

Original Research

11 August 2021

Changes in Wnt and TGF-β Signaling Mediate the Development of Regorafenib Resistance in Hepatocellular Carcinoma Cell Line HuH7

Mustafa Karabicici

, 4 more and

Esra Erdal

6,549 views

44 citations

Review

09 September 2021

Metabolic Contributions of Wnt Signaling: More Than Controlling Flight

Frederic Abou Azar

and

Gareth E. Lim

6,661 views

18 citations

Brief Research Report

18 August 2021

Receptor/Raft Ratio Is a Determinant for LRP6 Phosphorylation and WNT/β-Catenin Signaling

Fiete Haack

, 1 more and

Adelinde M. Uhrmacher

2,508 views

8 citations

Review

23 July 2021

WNT5B in Physiology and Disease

Sarocha Suthon

, 3 more and

Susan A. Krum

15,655 views

46 citations

Distribution and function of Fzd in neurons. (A) Schematic representation of localisation of Fzd receptors to different neuronal compartments. Fzd3 is localised to the soma, axons, and dendrites. Fzd4, Fzd7, and Fzd9 are present in dendrites and promote dendritogenesis and/or synaptogenesis. Fzd3, Fzd5, and Fzd9 play a role in axon outgrowth. Fzd4 is also involved in dendritogenesis. Fzd5 is present in axons where it regulates synapse formation. It is also present in dendrites but its function in this neuronal compartment is unknown. (B) Schematic representation of Fzd involved in synaptogenesis. Fzd3, Fzd1, and Fzd5 are presynaptically localised, whereas Fzd9 and Fzd7 are present postsynaptically. (C) Representation of asymmetric distribution of Fzd3 in growth cones due to the asymmetric localisation of Vangl2 at elongating filopodia. Here, Vangl2 promotes Fzd3 endocytosis and PCP signalling in certain filopodia to ensure asymmetric signalling for growth cone steering in response to Wnt gradients (Onishi et al., 2014). (A–C) Created with BioRender.com.

Review

03 August 2021

A Role for Frizzled and Their Post-Translational Modifications in the Mammalian Central Nervous System

Patricia Pascual-Vargas

and

Patricia C. Salinas

6,889 views

12 citations

Original Research

26 May 2021

Wnt3 Is Lipidated at Conserved Cysteine and Serine Residues in Zebrafish Neural Tissue

Divya Dhasmana

, 5 more and

Thorsten Wohland

4,016 views

11 citations

Correction

23 July 2021

Corrigendum: WNT5B in Physiology and Disease

Sarocha Suthon

, 3 more and

Susan A. Krum

1,880 views

2 citations

Review

06 May 2021

LRP5 and LRP6 in Wnt Signaling: Similarity and Divergence

Qian Ren

, 1 more and

Youhua Liu

The canonical Wnt/β-catenin signaling plays a fundamental role in regulating embryonic development, injury repair and the pathogenesis of human diseases. In vertebrates, low density lipoprotein receptor-related proteins 5 and 6 (LRP5 and LRP6), the single-pass transmembrane proteins, act as coreceptors of Wnt ligands and are indispensable for Wnt signal transduction. LRP5 and LRP6 are highly homologous and widely co-expressed in embryonic and adult tissues, and they share similar function in mediating Wnt signaling. However, they also exhibit distinct characteristics by interacting with different protein partners. As such, each of them possesses its own unique functions. In this review, we systematically discuss the similarity and divergence of LRP5 and LRP6 in mediating Wnt and other signaling in the context of kidney diseases. A better understanding of the precise role of LRP5 and LRP6 may afford us to identify and refine therapeutic targets for the treatment of a variety of human diseases.

25,773 views

109 citations

Mini Review

28 April 2021

WNT Ligand Dependencies in Pancreatic Cancer

Kristina Y. Aguilera

and

David W. Dawson

WNT signaling promotes the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) through wide-ranging effects on cellular proliferation, survival, differentiation, stemness, and tumor microenvironment. Of therapeutic interest is a genetically defined subset of PDAC known to have increased WNT/β-catenin transcriptional activity, growth dependency on WNT ligand signaling, and response to pharmacologic inhibitors of the WNT pathway. Here we review mechanisms underlying WNT ligand addiction in pancreatic tumorigenesis, as well as the potential utility of therapeutic approaches that functionally antagonize WNT ligand secretion or frizzled receptor binding.

9,515 views

43 citations