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Last update 08 May 2025

MRTFA

Last update 08 May 2025

Basic Info

Synonyms

BSAC, KIAA1438, MAL

+ [9]

Introduction

Transcription coactivator that associates with the serum response factor (SRF) transcription factor to control expression of genes regulating the cytoskeleton during development, morphogenesis and cell migration (PubMed:26224645). The SRF-MRTFA complex activity responds to Rho GTPase-induced changes in cellular globular actin (G-actin) concentration, thereby coupling cytoskeletal gene expression to cytoskeletal dynamics. MRTFA binds G-actin via its RPEL repeats, regulating activity of the MRTFA-SRF complex. Activity is also regulated by filamentous actin (F-actin) in the nucleus.

Drugs associated with MRTFA

CCG-203971

Target

MRTFA x SRF

Mechanism

MRTFA inhibitors [+1]

Active Org.

Genesis Biosciences LLC

Originator Org.

Genesis Biosciences LLC

Active Indication

Diabetes Mellitus, Type 2

Inactive Indication

Glaucoma, Open-Angle

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

CCG-257081

Target

MRTFA x NF-κB

Mechanism

MRTFA inhibitors [+1]

Active Org.

Fibrosix, Inc.

Originator Org.

Fibrosix, Inc.

Active Indication

Pneumonia [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

CCG-1423

Target

MRTFA x RHOA

Mechanism

MRTFA inhibitors [+1]

Active Org.

Kyoto University

Originator Org.

Kyoto University

Active Indication-

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with MRTFA

100 Translational Medicine associated with MRTFA

0 Patents (Medical) associated with MRTFA

702

Literatures (Medical) associated with MRTFA

01 May 2025·Matrix Biology

Inhibition of the MRTF-A/SRF signaling axis alleviates vocal fold scarring

Article

Author: Lefebvre, Véronique ; Truong, Huy D ; Friedman, Ryan M ; Zur, Karen B ; Chen, Jeffrey F ; Gottardi, Riccardo ; Brown, Elizabeth A ; Angelozzi, Marco ; Aronson, Matthew R

Vocal fold scarring, the most common cause of poor voice after airway injury, involves the transition of vocal fold fibroblasts to contractile myofibroblasts. Vocal fold myofibroblasts can be characterized by significant extracellular matrix (ECM) secretion and stress fiber formation. Biochemical signals, such as transforming growth factor (TGF)-β1, and biophysical cues, such as matrix stiffening, have been shown to induce the fibroblast-to-myofibroblast transition. To identify key intracellular pathways that may mediate myofibroblast activation, we performed bulk RNA sequencing of human vocal fold fibroblasts treated with or without TGF-β1 and found that genes downstream of myocardin related transcription factor A (MRTF-A) and serum response factor (SRF) were upregulated in TGFβ1-induced myofibroblasts. We then show that both TGF-β1 and ECM stiffening induce MRTF-A and SRF nuclear translocation during vocal fold myofibroblast activation. Inhibition of MRTF-A via CCG-257,081 reduced pro-fibrotic gene expression, the percentage of α-smooth muscle actin (α-SMA)-positive fibroblasts, and cell contractility in vitro. In a murine model of vocal fold scarring, MRTF-A inhibition reduced vocal fold scarring severity, evidenced by reduced epithelial thickening, decreased glycosaminoglycan content, and collagen deposition, and decreased expression of ACTA2. Our study suggests that the MRTF-A/SRF pathway regulates vocal fold myofibroblast activation, and that inhibition of MRTF-A has a protective effect against vocal fold scarring in mice.

14 Mar 2025·Cancer Research

MICAL2 Promotes Pancreatic Cancer Growth and Metastasis

Article

Author: Commisso, Cosimo ; Gallinger, Steven ; Sheik Pran Babu, Deepa ; Tamayo, Pablo ; Jang, Gun Ho ; Courelli, Asimina S. ; Sood, Divya ; Garg, Bharti ; Aggarwal, Neetu ; Martsinkovskiy, Alexei ; Goodfellow, Elliot ; D’Ippolito, Anthony ; Lambies, Guillem ; Johnston, Brian ; Lowy, Andrew M. ; Tiriac, Hervé ; Brodt, Pnina ; Jaque, Katelin ; Wenzel, Alexander T. ; Sharma, Shweta ; Gulay, Kevin Christian Montecillo ; Mesirov, Jill P. ; Patel, Jay ; Esparza, Edgar ; Khan, Sohini ; Austgen, Kathryn ; Rajbhandari, Nirakar ; Orlando, David A. ; Mose, Evangeline S. ; Panneerpandian, Ponmathi ; Jaquish, Dawn

AbstractPancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid cancers; thus, identifying more effective therapies is a major unmet need. In this study, we characterized the super-enhancer (SE) landscape of human PDAC to identify drivers of the disease that might be targetable. This analysis revealed MICAL2 as an SE-associated gene in human PDAC, which encodes the flavin monooxygenase enzyme that induces actin depolymerization and indirectly promotes serum response factor transcription by modulating the availability of serum response factor coactivators such as myocardin-related transcription factors (MRTF-A and MRTF-B). MICAL2 was overexpressed in PDAC, and high-MICAL2 expression correlated with poor patient prognosis. Transcriptional analysis revealed that MICAL2 upregulates KRAS and epithelial–mesenchymal transition signaling pathways, contributing to tumor growth and metastasis. In loss- and gain-of-function experiments in human and mouse PDAC cells, MICAL2 promoted both ERK1/2 and AKT activation. Consistent with its role in actin depolymerization and KRAS signaling, loss of MICAL2 also inhibited macropinocytosis. MICAL2, MRTF-A, and MRTF-B influenced PDAC cell proliferation and migration and promoted cell-cycle progression in vitro. Importantly, MICAL2 supported in vivo tumor growth and metastasis. Interestingly, MRTF-B, but not MRTF-A, phenocopied MICAL2-driven phenotypes in vivo. This study highlights the multiple ways in which MICAL2 affects PDAC biology and provides a foundation for future investigations into the potential of targeting MICAL2 for therapeutic intervention.Significance: Characterization of the epigenomic landscape of pancreatic cancer to identify early drivers of tumorigenesis uncovered MICAL2 as a super-enhancer–associated gene critical for tumor progression that represents a potential pharmacologic target.

01 Mar 2025·Life Sciences

Activation of megakaryocytic leukemia 1 in endothelial cells contributes to diabetic retinopathy in mice

Article

Author: Feng, Xiaofen ; Wang, Fei ; Ding, Yuhua ; Zhu, Yuwen

AIMSDiabetic retinopathy (DR) represents one of the most devastating sequences in patients with diabetes. Endothelial dysfunction is a key pathological feature of and contributing factor to DR. In the present study we investigated the role of megakaryocytic leukemia 1 (MKL1) in DR pathogenesis.METHODS AND MATERIALSDR was induced in mice by feeding with a high-fat diet (HFD). The Mkl1-Rosa26-KI mice were crossed to the Cdh5-Cre^ERT2 mice to generate endothelial-specific MKL1 knock-in mice (MKL1^EC-KI).KEY FINDINGSIn cultured human primary retinal endothelial cells exposure to high glucose promoted nuclear translocation of MKL1 without altering its mRNA or protein expression. MKL1 knockdown ameliorated whereas MKL1 over-expression exacerbated high glucose induced impairment of endothelial barrier function. Compared to wild type littermates, MKL1^EC-KI mice fed on HFD displayed worsened insulin resistance and accelerated DR pathogenesis. Consistently, administration of an MKL1 inhibitor CCG-1423 protected the mice from HFD feeding induced metabolic disorders and DR pathogenesis.SIGNIFICANCEOur data demonstrate that MKL1 may contribute to diabetic retinopathy by regulating endothelial behavior. Targeting MKL1 with small-molecule inhibitors can be considered as a therapeutic solution for the treatment of diabetic retinopathy.

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MRTFA

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