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.
Twomey
Erin
E
Neurogenesis and Brain Repair Group, Institute for Biological Sciences, National Research Council of Canada, 1200 Montreal Road, M-54, Ottawa, Canada ON K1A 0R6.
Li
Yan
Y
Lei
Joy
J
Sodja
Caroline
C
Ribecco-Lutkiewicz
Maria
M
Smith
Brandon
B
Fang
Hung
H
Bani-Yaghoub
Mahmud
M
McKinnell
Iain
I
Sikorska
Marianna
M
D000595:Amino Acid Sequence; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016384:Consensus Sequence / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D043263:Myosin-Light-Chain Phosphatase / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011485:Protein Binding / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000098563:Seven in Absentia Proteins
D015853:Cysteine Proteinase Inhibitors; D009687:Nuclear Proteins; D010446:Peptide Fragments; D061988:Proteasome Inhibitors; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D043263:Myosin-Light-Chain Phosphatase; C490372:PPP1R12A protein, human; D046988:Proteasome Endopeptidase Complex