FLNC Expression Level Influences the Activity of TEAD-YAP/TAZ Signaling

Abstract

Filamin C (FLNC), being one of the major actin-binding proteins, is involved in the maintenance of key muscle cell functions. Inherited skeletal muscle and cardiac disorders linked to genetic variants in FLNC have attracted attention because of their high clinical importance and possibility of genotype-phenotype correlations. To further expand on the role of FLNC in muscle cells, we focused on detailed alterations of muscle cell properties developed after the loss of FLNC. Using the CRISPR/Cas9 method we generated a C2C12 murine myoblast cell line with stably suppressed Flnc expression. FLNC-deficient myoblasts have a significantly higher proliferation rate combined with an impaired cell migration capacity. The suppression of Flnc expression leads to inability to complete myogenic differentiation, diminished expression of Myh1 and Myh4, alteration of transcriptional dynamics of myogenic factors, such as Mymk and Myog, and deregulation of Hippo signaling pathway. Specifically, we identified elevated basal levels of Hippo activity in myoblasts with loss of FLNC, and ineffective reduction of Hippo signaling activity during myogenic differentiation. The latter was restored by Flnc overexpression. In summary, we confirmed the role of FLNC in muscle cell proliferation, migration and differentiation, and demonstrated for the first time the direct link between Flnc expression and activity of TEAD-YAP\TAZ signaling. These findings support a role of FLNC in regulation of essential muscle processes relying on mechanical as well as signaling mechanisms.

Special Issue “Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy”

“…In this regard, the work of Knyazeva et al extends the knowledge of the role of Filamin C (FLNC) in muscle cells, focusing on muscle alterations developed after FLNC loss. The authors confirm the role of FLNC in the regulation of essential muscle processes such as muscle cell proliferation, migration, and differentiation [ 3 ]. Jorholt et al contribute to the clinical knowledge of ALPK3-associated cases by reporting two new cases of hypertrophic cardiomyopathy with muscle involvement and variability in age of onset [ 4 ].…”

Comprehensive analysis of tumor microenvironment and identification of an immune signature to predict the prognosis and immunotherapeutic response in lung squamous cell carcinoma

“…FLNC, a member of the actin-binding filamin protein family, is associated with lymphatic invasion and metastasis (31). FLNC is an important component of the cytoskeleton, and plays a role in cell adhesion and migration (32). However, to date, the role and mechanism of FLNC in lung cancer have not been demonstrated.…”

Bioinformatics Analysis of Immune Cell Infiltration Patterns and Potential Diagnostic Markers in Atherosclerosis

“…TPM2 has been identi ed as a potential diagnostic biomarker for atherosclerosis (28). FLNC expression levels affect the TEAD-YAP/TAZ signaling pathway (29). ITGA7 serves as a tumor suppressor gene in breast cancer (BC) and modulates BC invasion and migration (30).…”