The FERM domain-containing protein 6 (FRMD6), also known as Willin, is an upstream regulator of Hippo signaling that has recently been shown to modulate actin cytoskeleton dynamics and mechanical phenotype of neuronal cells through ERK signaling. Physiological functions of Willin/FRMD6 in the nervous system include neuronal differentiation, myelination, nerve injury repair, and vesicle exocytosis. The newly established neuronal role of Willin/FRMD6 is of particular interest given the mounting evidence suggesting a role for Willin/FRMD6 in Alzheimer's disease (AD), including a series of genome wide association studies that position Willin/FRMD6 as a novel AD risk gene. Here we describe recent findings regarding the role of Willin/FRMD6 in the nervous system and its actions in cellular perturbations related to the pathogenesis of AD.
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Willin/FRMD6 Mediates Mitochondrial Dysfunction Relevant to Neuronal Aβ Toxicity.
Cells
October 2022
School of Biology, University of St Andrews, St Andrews KY16 9TF, UK.
Willin/ has been reported as a potential Alzheimer's disease (AD) risk gene in a series of genome-wide association and neuroimaging studies; however, the mechanisms underlying its potential role in AD pathogenesis remain unknown. Here, we demonstrate the direct effects of Aβ on Willin/FRMD6 expression and position mitochondrial oxidative stress as a novel potential mechanism underlying the role of Willin/FRMD6 in AD pathogenesis. Specifically, using mouse hippocampal HT-22 cells and primary mouse neurons, we show that Aβ induces downregulation of Willin/FRMD6 protein expression.
View Article and Find Full Text PDFWillin/FRMD6: A Multi-Functional Neuronal Protein Associated with Alzheimer's Disease.
Cells
November 2021
School of Biology, University of St. Andrews, St. Andrews KY16 9TF, UK.
The FERM domain-containing protein 6 (FRMD6), also known as Willin, is an upstream regulator of Hippo signaling that has recently been shown to modulate actin cytoskeleton dynamics and mechanical phenotype of neuronal cells through ERK signaling. Physiological functions of Willin/FRMD6 in the nervous system include neuronal differentiation, myelination, nerve injury repair, and vesicle exocytosis. The newly established neuronal role of Willin/FRMD6 is of particular interest given the mounting evidence suggesting a role for Willin/FRMD6 in Alzheimer's disease (AD), including a series of genome wide association studies that position Willin/FRMD6 as a novel AD risk gene.
View Article and Find Full Text PDFWillin/FRMD6 Influences Mechanical Phenotype and Neuronal Differentiation in Mammalian Cells by Regulating ERK1/2 Activity.
Front Cell Neurosci
September 2020
Centre of Biophotonics, School of Biology, University of St Andrews, St Andrews, United Kingdom.
Willin/FRMD6 is part of a family of proteins with a 4.1 ezrin-radixin-moesin (FERM) domain. It has been identified as an upstream activator of the Hippo pathway and, when aberrant in its expression, is associated with human diseases and disorders.
View Article and Find Full Text PDFWillin, an upstream component of the hippo signaling pathway, orchestrates mammalian peripheral nerve fibroblasts.
PLoS One
November 2013
Medical and Biological Sciences Building, School of Medicine, University of St Andrews, St Andrews, United Kingdom.
Willin/FRMD6 was first identified in the rat sciatic nerve, which is composed of neurons, Schwann cells, and fibroblasts. Willin is an upstream component of the Hippo signaling pathway, which results in the inactivation of the transcriptional co-activator YAP through Ser127 phosphorylation. This in turn suppresses the expression of genes involved in cell growth, proliferation and cancer development ensuring the control of organ size, cell contact inhibition and apoptosis.
View Article and Find Full Text PDFWillin/FRMD6 expression activates the Hippo signaling pathway kinases in mammals and antagonizes oncogenic YAP.
Oncogene
January 2012
School of Biology, University of St Andrews, St Andrews, UK.
The Salvador/Warts/Hippo (Hippo) signaling pathway defines a novel signaling cascade regulating cell contact inhibition, organ size control, cell growth, proliferation, apoptosis and cancer development in mammals. The Drosophila melanogaster protein Expanded acts in the Hippo signaling pathway to control organ size. Previously, willin/FRMD6 has been proposed as the human orthologue of Expanded.
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