Overexpression of TNNI3K, a cardiac-specific MAPKKK, promotes cardiac dysfunction.

Abstract

Cardiac troponin I-interacting kinase (TNNI3K) is a cardiac-specific kinase whose biological function remains largely unknown. We have recently shown that TNNI3K expression greatly accelerates cardiac dysfunction in mouse models of cardiomyopathy, indicating an important role in modulating disease progression. To further investigate TNNI3K kinase activity in vivo, we have generated transgenic mice expressing both wild-type and kinase-dead versions of the human TNNI3K protein. Importantly, we show that the increased TNNI3K kinase activity induces mouse cardiac remodeling, and its kinase activity promotes accelerated disease progression in a left-ventricular pressure overload model of mouse cardiomyopathy. Using an in vitro kinase assay and proteomics analysis, we show that TNNI3K is a dual-function kinase with Tyr and Ser/Thr kinase activity. TNNI3K expression induces a series of cellular and molecular changes, including a reduction of sarcomere length and changes in titin isoform composition, which are indicative of cardiac remodeling. Using antisera to TNNI3K, we show that TNNI3K protein is located at the sarcomere Z disc. These combined data suggest that TNNI3K mediates cell signaling to modulate cardiac response to stress.

• Authors: Hao Tang, Kunhong Xiao, Lan Mao, Howard A Rockman, Douglas A Marchuk
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 54 Pg. 101-11 (Jan 2013) ISSN: 1095-8584 [Electronic] England
• PMID: 23085512 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Connectin
• Muscle Proteins
• Peptide Fragments
• Protein Isoforms
• TTN protein, human
• Protein Kinases
• Protein Serine-Threonine Kinases
• TNNI3K protein, human
• MAP Kinase Kinase Kinases

Topics

• Amino Acid Sequence
• Animals
• Connectin
• Female
• Gene Expression
• HEK293 Cells
• Humans
• MAP Kinase Kinase Kinases (chemistry, genetics, metabolism)
• Male
• Mice
• Mice, Inbred DBA
• Mice, Transgenic
• Molecular Sequence Data
• Muscle Proteins (metabolism)
• Myocardium (enzymology, pathology)
• Myocytes, Cardiac (enzymology, physiology)
• Organ Size
• Organelle Size
• Peptide Fragments (chemistry)
• Phosphorylation
• Protein Isoforms (metabolism)
• Protein Kinases (metabolism)
• Protein Processing, Post-Translational
• Protein Serine-Threonine Kinases
• Sarcomeres (enzymology, pathology)
• Signal Transduction
• Stress, Physiological
• Ventricular Dysfunction, Left (enzymology, pathology)
• Ventricular Remodeling