Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk

Genes Dis. 2023 Mar 24;11(1):103-134. doi: 10.1016/j.gendis.2023.01.030.

Kevin Qin ¹ ², Michael Yu ¹ ², Jiaming Fan ² ³, Hongwei Wang ², Piao Zhao ² ⁴, Guozhi Zhao ² ⁴, Wei Zeng ² ⁵, Connie Chen ², Yonghui Wang ² ⁶, Annie Wang ² ⁷, Zander Schwartz ² ⁸, Jeffrey Hong ², Lily Song ², William Wagstaff ², Rex C Haydon ², Hue H Luu ², Sherwin H Ho ², Jason Strelzow ², Russell R Reid ² ⁷, Tong-Chuan He ² ⁷, Lewis L Shi ²

Affiliations

1 Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
2 Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA.
3 Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China.
4 Departments of Orthopaedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
5 Department of Interventional Neurology, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong 523475, China.
6 Department of Clinical Laboratory Medicine, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China.
7 Laboratory of Craniofacial Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA.
8 School of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA.

PMID: 37588235 DOI: 10.1016/j.gendis.2023.01.030

Abstract

Wnt signaling plays a major role in regulating cell proliferation and differentiation. The Wnt ligands are a family of 19 secreted glycoproteins that mediate their signaling effects via binding to Frizzled receptors and LRP5/6 coreceptors and transducing the signal either through β-catenin in the canonical pathway or through a series of Other proteins in the noncanonical pathway. Many of the individual components of both canonical and noncanonical Wnt signaling have additional functions throughout the body, establishing the complex interplay between Wnt signaling and Other signaling pathways. This crosstalk between Wnt signaling and Other pathways gives Wnt signaling a vital role in many cellular and organ processes. Dysregulation of this system has been implicated in many diseases affecting a wide array of organ systems, including Cancer and embryological defects, and can even cause embryonic lethality. The complexity of this system and its interacting proteins have made Wnt signaling a target for many therapeutic treatments. However, both stimulatory and inhibitory treatments come with potential risks that need to be addressed. This review synthesized much of the current knowledge on the Wnt signaling pathway, beginning with the history of Wnt signaling. It thoroughly described the different variants of Wnt signaling, including canonical, noncanonical Wnt/PCP, and the noncanonical Wnt/CA²⁺ pathway. Further description involved each of its components and their involvement in Other cellular processes. Finally, this review explained the various Other pathways and processes that crosstalk with Wnt signaling.

Keywords

Canonical Wnt; Noncanonical Wnt; Signal transduction; Signaling crosstalk; β-catenin.

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