A novel mechanism involving four-and-a-half LIM domain protein-1 and extracellular signal-regulated kinase-2 regulates titin phosphorylation and mechanics

J Biol Chem. 2012 Aug 24;287(35):29273-84. doi: 10.1074/jbc.M112.372839. Epub 2012 Jul 9.

Abstract

Understanding mechanisms underlying titin regulation in cardiac muscle function is of critical importance given recent compelling evidence that highlight titin mutations as major determinants of human cardiomyopathy. We previously identified a cardiac biomechanical stress-regulated complex at the cardiac-specific N2B region of titin that includes four-and-a-half LIM domain protein-1 (Fhl1) and components of the mitogen-activated protein signaling cascade, which impacted muscle compliance in Fhl1 knock-out cardiac muscle. However, direct regulation of these molecular components in mediating titin N2B function remained unresolved. Here we identify Fhl1 as a novel negative regulator of titin N2B levels and phosphorylation-mediated mechanics. We specifically identify titin N2B as a novel substrate of extracellular signal regulated-kinase-2 (Erk2) and demonstrate that Fhl1 directly interferes with Erk2-mediated titin-N2B phosphorylation. We highlight the critical region in titin-N2B that interacts with Fhl1 and residues that are dependent on Erk2-mediated phosphorylation in situ. We also propose a potential mechanism for a known titin-N2B cardiomyopathy-causing mutation that involves this regulatory complex. These studies shed light on a novel mechanism regulating titin-N2B mechano-signaling as well as suggest that dysfunction of these pathways could be important in cardiac disease states affecting muscle compliance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomyopathies / metabolism
  • Cardiomyopathies / pathology
  • Connectin
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • LIM Domain Proteins / genetics
  • LIM Domain Proteins / metabolism*
  • Mechanotransduction, Cellular*
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Mutation
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Phosphorylation
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Protein Structure, Tertiary

Substances

  • Connectin
  • FHL1 protein, human
  • Fhl1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • LIM Domain Proteins
  • Muscle Proteins
  • TTN protein, human
  • Protein Kinases
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1