MRTFA: A critical protein in normal and malignant hematopoiesis and beyond

Abstract

Myocardin-related transcription factor A (MRTFA) is a coactivator of serum response factor, a transcription factor that participates in several critical cellular functions including cell growth and apoptosis. MRTFA couples transcriptional regulation to actin cytoskeleton dynamics, and the transcriptional targets of the MRTFA-serum response factor complex include genes encoding cytoskeletal proteins as well as immediate early genes. Previous work has shown that MRTFA promotes the differentiation of many cell types, including various types of muscle cells and hematopoietic cells, and MRTFA's interactions with other protein partners broaden its cellular roles. However, despite being first identified as part of the recurrent t(1;22) chromosomal translocation in acute megakaryoblastic leukemia, the mechanisms by which MRTFA functions in malignant hematopoiesis have yet to be defined. In this review, we provide an in-depth examination of the structure, regulation, and known functions of MRTFA with a focus on hematopoiesis. We conclude by identifying areas of study that merit further investigation.

Keywords: G-actin; Ras homolog gene family member A; cell differentiation; cytoskeleton; hematopoiesis; leukemia; myocardin; platelet; serum response factor.

Figure 1

The five transcript variants of human MRTFA, including translation start and stop sites as well as locations of each of the five domains and their corresponding exons. Below each transcript is a schematic of the protein encoded by the variant with critical domains indicated. hMRTFA, human MRTFA; MRTFA, myocardin-related transcription factor A; TV, transcript variant.

Figure 2

Comparison of MRTFA, MRTFB, and myocardin structures, displaying the location of each conserved domain described in the text. Note that noncanonical RPEL-like domains have little to no actin binding. Amino acid sequence similarities (% identity) between myocardin family proteins within the key domains are shown. hMRTFA, human MRTFA; MRTFA, myocardin-related transcription factor A; TV, transcript variant.

Figure 3

Schematic representation of MRTFA activation and regulation as well as interactions with its various transcriptional partners. H3K4, histone 3 lysine 4; MRTFA, myocardin-related transcription factor A; SRF, serum response factor.

Figure 4

Overview of MRTFA KO mice developed by Li et al (71) and Sun et al. (72), including their respective exon deletions. Below each transcript is a schematic of the predicted protein encoded by the variant with critical domains indicated. LZ, leucine-zipper; MRTFA, myocardin-related transcription factor A; TAD, transcriptional activation domain.