Abstract
Wnt5a is involved in activating several non-canonical WNT signaling pathways, through binding to different members of the Frizzled- and Ror-family receptors. Wnt5a signaling is critical for regulating normal developmental processes, including proliferation, differentiation, migration, adhesion and polarity. However, the aberrant activation or inhibition of Wnt5a signaling is emerging as an important event in cancer progression, exerting both oncogenic and tumor suppressive effects. Recent studies show the involvement of Wnt5a in regulating cancer cell invasion, metastasis, metabolism and inflammation. In this article, we review findings regarding the molecular mechanisms and roles of Wnt5a signaling in various cancer types, and highlight Wnt5a in ovarian cancer.
Highlights
Wnt signaling represents a group of signaling pathways that regulate a diversity of processes fundamental to normal development, including cell proliferation, differentiation, polarity, adhesion and motility [1,2]
Senescence is the arrest of cell growth, which can be caused by critically shortened telomeres, activated oncogenes such as HRas, DNA damage, and certain cancer therapeutics such as cisplatin [27,28]
Wnt5a produced by mammary luminal cells acts in a paracrine fashion, through binding to receptor tyrosine kinase (Ryk) receptor on basal tumor initiating cells (TICs) and forms a complex with transforming growth factor β receptor 1 (TGFβR1), leading to the phosphorylation and activation of SMAD2, a signaling protein involved in regulating cell differentiation, and suppression of basal cells growth and tumor initiation [46]
Summary
Wnt signaling represents a group of signaling pathways that regulate a diversity of processes fundamental to normal development, including cell proliferation, differentiation, polarity, adhesion and motility [1,2]. Wnt5a activation of the Wnt/Ca2+ pathway results in the mobilization of free intracellular calcium that regulates many cellular processes, including actin cytoskeleton remodeling and cell motility through activation of calcium-dependent signaling molecules, such as calmodulin dependent protein Kinase II (CAMKII) and protein kinase C (PKC) [20,21,22,23,24]. The diversity of Wnt5a binding receptors and the cell/tissue of origin likely contribute to triggering distinct signaling pathways (Figure 1A,B) [8]. Another factor that may play a role in regulation of Wnt5a-activated signaling is the presence of a specific Wnt5a isoform within the tissue. We will discuss regarding the molecular mechanisms and the emerging roles of Wnt5a signaling in various cancer types
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