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PKA, PKC, and the protein phosphatase 2A influence HAND factor function: a mechanism for tissue-specific transcriptional regulation.

The bHLH factors HAND1 and HAND2 are required for heart, vascular, neuronal, limb, and extraembryonic development. Unlike most bHLH proteins, HAND factors exhibit promiscuous dimerization properties. We report that phosphorylation/dephosphorylation via PKA, PKC, and a specific heterotrimeric protein phosphatase 2A (PP2A) modulates HAND function. The PP2A targeting-subunit B56delta specifically interacts with HAND1 and -2, but not other bHLH proteins. PKA and PKC phosphorylate HAND proteins in vivo, and only B56delta-containing PP2A complexes reduce levels of HAND1 phosphorylation. During RCHOI trophoblast stem cell differentiation, B56delta expression is downregulated and HAND1 phosphorylation increases. Mutations in phosphorylated residues result in altered HAND1 dimerization and biological function. Taken together, these results suggest that site-specific phosphorylation regulates HAND factor functional specificity.

Pubmed ID: 14636580


  • Firulli BA
  • Howard MJ
  • McDaid JR
  • McIlreavey L
  • Dionne KM
  • Centonze VE
  • Cserjesi P
  • Virshup DM
  • Firulli AB


Molecular cell

Publication Data

November 25, 2003

Associated Grants

  • Agency: NHLBI NIH HHS, Id: 2R01HL61677-05
  • Agency: NIDDK NIH HHS, Id: DK57237
  • Agency: NCI NIH HHS, Id: R01 CA80809
  • Agency: NHLBI NIH HHS, Id: R01 HL061677
  • Agency: NHLBI NIH HHS, Id: R01 HL061677-05
  • Agency: NHLBI NIH HHS, Id: R01 HLA61677-01A1
  • Agency: NINDS NIH HHS, Id: R01 NS40644

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Differentiation
  • Cell Line
  • Chick Embryo
  • Cyclic AMP-Dependent Protein Kinases
  • DNA-Binding Proteins
  • Dimerization
  • Gene Expression Regulation, Developmental
  • Genes, Reporter
  • Helix-Loop-Helix Motifs
  • Humans
  • Molecular Sequence Data
  • Morphogenesis
  • Phosphoprotein Phosphatases
  • Phosphorylation
  • Protein Kinase C
  • Protein Phosphatase 2
  • Protein Subunits
  • Recombinant Fusion Proteins
  • Sequence Alignment
  • Stem Cells
  • Transcription Factors
  • Transcription, Genetic
  • Two-Hybrid System Techniques
  • Zebrafish Proteins