MRTFB (myocardin-related transcription factor B) functions as a transcriptional coactivator of serum response factor (SRF) that links actin cytoskeleton dynamics to gene expression. 1 MRTFB contains N-terminal actin-binding motifs and translocates to the nucleus upon Rho signaling-mediated release from G-actin, increasing SRF-dependent transcription. 1 In pancreatic cancer, MRTFB is modulated by MICAL2-induced actin depolymerization; notably, MRTFB alone phenocopies MICAL2-driven tumor growth and metastasis in vivo. 2 Conversely, MRTFB acts as a tumor suppressor in colorectal cancer by transcriptionally activating MCAM and SPDL1, genes that inhibit cell invasion and migration. 3 In smooth muscle cells, MRTFB suppresses inflammation by inactivating TBK1 kinase, providing defense against pro-inflammatory insults. 4 MRTFB mediates neuronal plasticity downstream of BDNF signaling, regulating dendritic morphology and gene expression essential for learning and memory. 1 Pathologically, MRTFB gene fusions with CRTC1 or TEAD1 drive myxoid mesenchymal neoplasms with myogenic differentiation. 5 6 De novo gain-of-function variants (R104G, A91P) in MRTFB cause decreased actin binding and increased transcriptional activity, resulting in a novel neurodevelopmental disorder with intellectual disability and dysmorphic features. 7 MRTFB also contributes to HIV-1 latency establishment. 8