Regulation of MYPT1 stability by the E3 ubiquitin ligase SIAH2.
Myosin phosphatase target subunit 1 (MYPT1), together with catalytic subunit of type1 delta isoform (PP1cdelta) and a small 20-kDa regulatory unit (M20), form a heterotrimeric holoenzyme, myosin phosphatase (MP), which is responsible for regulating the extent of myosin light chain phosphorylation. Here we report the identification and characterization of a ... molecular interaction between Seven in absentia homolog 2 (SIAH2) and MYPT1 that resulted in the proteasomal degradation of the latter in mammalian cells, including neurons and glia. The interaction involved the substrate binding domain of SIAH2 (aa 116-324) and a central region of MYPT1 (aa 445-632) containing a degenerate consensus Siah-binding motif RLAYVAP (aa 493-499) evolutionally conserved from fish to humans. These findings suggest a novel mechanism whereby the ability of MP to modulate myosin light chain might be regulated by the degradation of its targeting subunit MYPT1 through the SIAH2-ubiquitin-proteasomal pathway. In this manner, the turnover of MYPT1 would serve to limit the duration and/or magnitude of MP activity required to achieve a desired physiological effect.
Mesh Terms:
Amino Acid Sequence, Animals, Astrocytes, Binding Sites, Cell Line, Cell Line, Tumor, Cells, Cultured, Consensus Sequence, Cysteine Proteinase Inhibitors, Cytoplasm, Gene Expression, Humans, Mice, Mice, Inbred Strains, Molecular Sequence Data, Mutation, Myosin-Light-Chain Phosphatase, Neurons, Nuclear Proteins, Peptide Fragments, Proteasome Endopeptidase Complex, Protein Binding, Protein Interaction Domains and Motifs, Protein Isoforms, Recombinant Fusion Proteins, Sequence Homology, Amino Acid, Transfection, Two-Hybrid System Techniques, Ubiquitin-Protein Ligases
Amino Acid Sequence, Animals, Astrocytes, Binding Sites, Cell Line, Cell Line, Tumor, Cells, Cultured, Consensus Sequence, Cysteine Proteinase Inhibitors, Cytoplasm, Gene Expression, Humans, Mice, Mice, Inbred Strains, Molecular Sequence Data, Mutation, Myosin-Light-Chain Phosphatase, Neurons, Nuclear Proteins, Peptide Fragments, Proteasome Endopeptidase Complex, Protein Binding, Protein Interaction Domains and Motifs, Protein Isoforms, Recombinant Fusion Proteins, Sequence Homology, Amino Acid, Transfection, Two-Hybrid System Techniques, Ubiquitin-Protein Ligases
Exp. Cell Res.
Date: Jan. 01, 2010
PubMed ID: 19744480
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