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Interaction between TAK1-TAB1-TAB2 and RCAN1-calcineurin defines a signalling nodal control point

Qinghang Liu1, Jennifer Caldwell Busby, Jeffery D Molkentin

  • 1Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, and the Howard Hughes Medical Institute, Cincinnati, Ohio 45229, USA.

Nature Cell Biology
|January 13, 2009
PubMed

Insights

Regulator of calcineurin (RCAN) controls calcineurin activity. This study reveals TAK1-TAB1-TAB2 complex phosphorylates RCAN1, switching it from inhibitor to facilitator of calcineurin-NFAT signaling and cardiomyocyte growth.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Cardiovascular research

Background:

  • Calcineurin, a calcium-activated protein phosphatase, is regulated by RCANs across species.
  • The interaction between RCANs and TAK1-TAB1-TAB2 complex is not well understood.

Purpose of the Study:

  • To elucidate the molecular mechanism by which TAK1-TAB1-TAB2 regulates calcineurin-NFAT signaling.
  • To investigate the role of TAK1-TAB1-TAB2 in RCAN1-mediated control of calcineurin activity and cardiomyocyte growth.

Main Methods:

  • Yeast two-hybrid screening to identify interacting partners of RCAN1.
  • In vitro and in vivo interaction assays to confirm protein-protein interactions.
  • Phosphorylation site mapping and functional assays in cell cultures and cardiomyocytes.

Main Results:

  • TAB2 was identified as an RCAN1-interacting protein, forming a macromolecular complex with TAK1, TAB1, and calcineurin.
  • TAK1 phosphorylates RCAN1 at Ser94 and Ser136, converting it from a calcineurin inhibitor to a facilitator.
  • This phosphorylation enhances NFATc1 translocation, transcriptional activation, and cardiomyocyte hypertrophy.
  • TAK1 is essential for calcineurin-induced cardiomyocyte growth, and calcineurin dephosphorylates and inhibits TAK1/TAB1.

Conclusions:

  • TAK1-TAB1-TAB2 complex directly phosphorylates RCAN1, thereby promoting calcineurin-NFAT signaling and cardiomyocyte hypertrophy.
  • Calcineurin activation reciprocally inhibits TAK1 signaling through dephosphorylation.
  • This study reveals a novel cross-regulatory mechanism between TAK1 and calcineurin signaling pathways crucial for cardiomyocyte growth.

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