The myocardin-related transcription factor MKL co-regulates the cellular levels of two profilin isoforms

J Biol Chem. 2017 Jul 14;292(28):11777-11791. doi: 10.1074/jbc.M117.781104. Epub 2017 May 25.

Abstract

Megakaryoblastic leukemia (MKL)/serum-response factor (SRF)-mediated gene transcription is a highly conserved mechanism that connects dynamic reorganization of the actin cytoskeleton to regulation of expression of a wide range of genes, including SRF itself and many important structural and regulatory components of the actin cytoskeleton. In this study, we examined the possible role of MKL/SRF in the context of regulation of profilin (Pfn), a major controller of actin dynamics and actin cytoskeletal remodeling in cells. We demonstrated that despite being located on different genomic loci, two major isoforms of Pfn (Pfn1 and Pfn2) are co-regulated by a common mechanism involving the action of MKL that is independent of its SRF-related activity. We found that MKL co-regulates the expression of Pfn isoforms indirectly by modulating signal transducer and activator of transcription 1 (STAT1) and utilizing its SAP-domain function. Unexpectedly, our studies revealed that cellular externalization, rather than transcription of Pfn1, is affected by the perturbations of MKL. We further demonstrated that MKL can influence cell migration by modulating Pfn1 expression, indicating a functional connection between MKL and Pfn1 in actin-dependent cellular processes. Finally, we provide initial evidence supporting the ability of Pfn to influence MKL and SRF expression. Collectively, these findings suggest that Pfn may play a role in a possible feedback loop of the actin/MKL/SRF signaling circuit.

Keywords: MKL; SAP-domain; actin; cell migration; cytoskeleton; profilin; serum-response factor (SRF).

MeSH terms

  • Cell Line, Tumor
  • Cell Movement
  • Gene Expression Regulation*
  • HEK293 Cells
  • Humans
  • Oligopeptides / genetics
  • Oligopeptides / metabolism
  • Profilins / genetics
  • Profilins / metabolism*
  • Protein Interaction Domains and Motifs
  • Protein Transport
  • RNA Interference
  • RNA, Messenger / metabolism
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • STAT1 Transcription Factor / antagonists & inhibitors
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism*
  • Serum Response Factor / antagonists & inhibitors
  • Serum Response Factor / genetics
  • Serum Response Factor / metabolism
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*

Substances

  • MRTFA protein, human
  • Oligopeptides
  • PFN1 protein, human
  • PFN2 protein, human
  • Profilins
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • SRF protein, human
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Serum Response Factor
  • Trans-Activators
  • FLAG peptide