Received: 22 October 2021 | Revised: 10 February 2022 | Accepted: 7 March 2022 DOI: 10.1002/cbin.11797 REVIEW Wnt signaling pathway: A comprehensive review Rabia Hayat 1 | Maleeha Manzoor 2 | Ali Hussain 3 1 Institute of Evolution and Marine Biodiversity, Ocean University of China, Qingdao, China 2 Department of Zoology, Government College University, Faisalabad, Pakistan 3 Department of Wildlife and Ecology, University of Veterinary and Animal Sciences, Lahore, Pakistan Correspondence Maleeha Manzoor, Department of Zoology, Government College University, Faisalabad, Pakistan. Email: maleehamanzoor@gcuf.edu.pk Abstract Wnt signaling is an evolutionary cell‐to‐cell coordination mechanism and it is highly critical for a variety of physiological processes of an organism's body, including stem cell regeneration, proliferation, division, migration, polarity of a cell, determining fate of the cell and specification of neural crest, neural symmetry and morphogenesis. Wnts are extracellular secreted glycol proteins, consisted of a family of 19 human proteins that represent the complex nature of the regulatory structure and physiological efficiency of signaling. Moreover, a Wnt/β‐catenin‐dependent path- way and the β‐catenin‐independent pathway that is further classified into the Planar Cell Polarity and Wnt/Ca 2+ pathways have been established as key signaling nodes downstream of the frizzled (Fz/Fzd) receptor, and these nodes are extensively analyzed at biochemical and molecular levels. Genetic and epigenetic activities that ultimately characterize the pathway and its subsequent responses contribute to Wnt‐β‐catenin signaling pathway hypo or hyper‐activation and is associated with the variety of human disorders progression most significantly cancers. Recognizing how this mechanism operates is crucial to the advancement of cancer prevention therapies or regenerative medicine methods. KEYWORDS cancer, Wnt proteins, Wnt signaling, Wnt/Ca 2+ , Wnt/β‐catenin‐dependent 1 | INTRODUCTION Extensive research work has been dedicated to analyze the signaling pathways and molecular processes that regulate an organism's growth in the new era of molecular medicine. In the current research, this focus is profoundly intertwined and leads to the idea that identifying the processes that govern natural development will raise our expectations enormously to deter and manage the pleiotropic disorders that appear when such pathways go faulty. The Wnt signaling is among the key pathways about which much work has been put into delineating (Zhan et al., 2017). An image of a signaling cascade that is entirely crucial for the developmental process of all complex organisms along with the development and repair of different tissue types has been drawn over 40 years of scientific investigations in various model organisms. While our knowledge of this complex pathway is indeed very limited, without such initial efforts, we might not be here as we are currently. Researchers from multiple fields, that is, evolutionary biologists to cellular biologists as well as from embryologists to challenging biochemists, have contributed important knicks and knacks to crack the biological puzzles of Wnt signaling. And if we developed deeper insights about Wnt proteins biological functions, we can more effectively identify and understand the abnormal signaling which ultimately help us to recognize its role in the etiology of several diseases like structural and metabolic disturbances to various types of tumors (Nusse & Clevers, 2017, Wiese et al., 2018). The title Wnt has been derived by combining designations of wingless (Wg) polarity gene of Drosophila segment and homolog of vertebrate, integrated or int‐1 (Holstein, 2012; Logan & Nusse, 2004; Wodarz & Nusse, 1998). From an evolutionary point of view, Wnt signaling is highly conserved and contributes significantly to embryogenesis, homeostasis and regen- eration of adult tissues (Nusse & Clevers, 2017). It is also crucial for maintaining genetic stability as well as play major role in determining fate of the cell, differentiation, apoptosis and motility of cells along Cell Biol Int. 2022;1–15. wileyonlinelibrary.com/journal/cbin © 2022 International Federation for Cell Biology | 1 C Cell ell B Biology iology I International nternational