Last update 01 Nov 2024

MRTFA

Last update 01 Nov 2024

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 [+3]

Originator Org.

Genesis Biosciences LLC

Active Indication

Glaucoma, Open-Angle [+1]

Inactive Indication-

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

703

Literatures (Medical) associated with MRTFA

01 Nov 2024·Molecular Neurobiology

Overexpression of α-Klotho isoforms promotes distinct Effects on BDNF-Induced Alterations in Dendritic Morphology

Article

Author: Sadovnik, Ratchell ; Firestein, Bonnie L ; Gandu, Srinivasa ; Suresh, Shradha ; Fu, Allen ; Cararo-Lopes, Marina Minto

Abstractα-Klotho (α-Kl) is a modulator of aging, neuroprotection, and cognition. Transcription of the Klotho gene produces two splice variants—a membrane protein (mKl), which can be cleaved and released into the extracellular milieu, and a truncated secreted form (sKl). Despite mounting evidence supporting a role for α-Kl in brain function, the specific roles of α-Kl isoforms in neuronal development remain elusive. Here, we examined α-Kl protein levels in rat brain and observed region-specific expression in the adult that differs between isoforms. In the developing hippocampus, levels of isoforms decrease after the third postnatal week, marking the end of the critical period for development. We overexpressed α-Kl isoforms in primary cultures of rat cortical neurons and evaluated effects on brain-derived neurotrophic factor (BDNF) signaling. Overexpression of either isoform attenuated BDNF-mediated signaling and reduced intracellular Ca2+ levels, with mKl promoting a greater effect. mKl or sKl overexpression in hippocampal neurons resulted in a partially overlapping reduction in secondary dendrite branching. Moreover, mKl overexpression increased primary dendrite number. BDNF treatment of neurons overexpressing sKl resulted in a dendrite branching phenotype similar to control neurons. In neurons overexpressing mKl, BDNF treatment restored branching of secondary and higher order dendrites close, but not distal, to the soma. Taken together, the data presented support the idea that sKl and mKl play distinct roles in neuronal development, and specifically, in dendrite morphogenesis.

01 Nov 2024·Life Sciences

Macrophage MKL1 contributes to cardiac fibrosis in a mouse model of myocardial infarction

Article

Author: Kuai, Yameng ; Yu, Wenkui ; Cao, Ke ; Zhu, Yuwen ; Chen, Baoyu ; Zhao, Qianwen

AIMSCardiac fibrosis is characterized by aberrant collagen deposition in the heart. Macrophage polarization or infiltration is the main reason to accelerate the collagen deposition. We attempted to investigate the involvement of MKL1 in macrophages during the development of cardiac fibrosis.MATERIALS AND METHODSCardiac fibrosis is induced by myocardial infarction (MI). The MKL1^f/f mice were crossed to the Lyz2-cre mice to generate macrophage conditional MKL1 knockout mice (MKL1^ΔMφ). In addition, macrophage conditional MKL1 overexpression mice (MKL1^Mϕ-OE) were constructed by crossing Lyz2-cre mice to MKL1^{ΔN200-Rosa26} mice.KEY FINDINGSMKL1 expression was significantly increased in macrophages of both ischemic cardiomyopathy (ICM) patients and mice induced to develop myocardial infarction. Deletion of MKL1 in macrophages improved the heart function after MI-induced cardiac fibrosis. Consistently, MKL1^Mϕ-OE mice displayed more severe cardiac fibrosis and worsened heart function than the control mice after MI. Moreover, administration of a small-molecule MKL1 inhibitor CCG-1423 also decreased the collagen deposition after MI.SIGNIFICANCEOur data demonstrate that MKL1 in macrophages contributes to cardiac fibrosis pathogenesis and reinforce the notion that targeting MKL1 may yield effective antifibrotic therapeutics in the heart.

01 Oct 2024·Molecular Biology of the Cell

mDia2 is an important mediator of MRTF-A-dependent regulation of breast cancer cell migration

Article

Author: Joy, Marion ; Chawla, Pooja ; Lucas, Peter C. ; Roy, Partha ; Chen, Fangyuan ; Yu, Virginia ; Gau, David ; Antonello, Jacob ; Lee, Adrian V. ; Boone, David ; Eder, Ian

Dysregulated actin cytoskeleton gives rise to aberrant cell motility and metastatic spread of tumor cells. This study evaluates the effect of overexpression of wild-type versus functional mutants of MRTF-A on migration and invasion of breast cancer (BC) cells. Our studies indicate that SRF's interaction is critical for MRTF-A-induced promotion of both two-dimensional and three-dimensional cell migration, while the SAP-domain function is important selectively for three-dimensional cell migration. Increased MRTF-A activity is associated with more effective membrane protrusion, a phenotype that is attributed predominantly to SRF's interaction with MRTF. We demonstrate formin-family protein mDia2 as an important mediator of MRTF-stimulated actin polymerization at the leading edge and cell migration. Multiplexed quantitative immunohistochemistry and transcriptome analyses of clinical BC specimens further demonstrate a positive correlation between nuclear localization of MRTF with malignant traits of cancer cells and enrichment of MRTF–SRF gene signature in pair-matched distant metastases versus primary tumors. In conclusion, this study establishes a novel mechanism of MRTF-dependent regulation of cell migration and provides evidence for the association between MRTF activity and increased malignancy in human BC, justifying future development of specific small molecule inhibitors of the MRTF-SRF transcriptional complex as potential therapeutic agents in BC.

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MRTFA

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