NM23-H1 Tumor Suppressor Physically Interacts with Serine-Threonine Kinase Receptor-associated Protein, a Transforming Growth Factor-β (TGF-β) Receptor-interacting Protein, and Negatively Regulates TGF-β Signaling
Copyright policy )NM23-H1 Tumor Suppressor Physically Interacts with Serine-Threonine Kinase Receptor-associated Protein, a Transforming Growth Factor-β (TGF-β) Receptor-interacting Protein, and Negatively Regulates TGF-β Signaling
NM23-H1 is a member of the NM23/NDP kinase gene family and a putative metastasis suppressor. Previously, a screen for NM23-H1-interacting proteins that could potentially modulate its activity identified serine-threonine kinase receptor-associated protein (STRAP), a transforming growth factor (TGF)-beta receptor-interacting protein. Through the use of cysteine to serine amino acid substitution mutants of NM23-H1 (C4S, C109S, and C145S) and STRAP (C152S, C270S, and C152S/C270S), we demonstrated that the association between these two proteins is dependent on Cys(145) of NM23-H1 and Cys(152) and Cys(270) of STRAP but did not appear to involve Cys(4) and Cys(109) of NM23-H1, suggesting that a disulfide linkage involving Cys(145) of NM23-H1 and Cys(152) or Cys(270) of STRAP mediates complex formation. The interaction was dependent on the presence of dithiothreitol or beta-mercaptoethanol but not H(2)O(2). Ectopic expression of wild-type NM23-H1, but not NM23-H1(C145S), negatively regulated TGF-beta signaling in a dose-dependent manner, enhanced stable association between the TGF-beta receptor and Smad7, and prevented nuclear translocation of Smad3. Similarly, wild-type NM23-H1 inhibited TGF-beta-induced apoptosis and growth inhibition, whereas NM23-H1(C145S) had no effect. Knockdown of NM23-H1 by small interfering RNA stimulated TGF-beta signaling. Coexpression of wild-type STRAP, but not STRAP(C152S/C270S), significantly stimulated NM23-H1-induced growth of HaCaT cells. These results suggest that the direct interaction of NM23-H1 and STRAP is important for the regulation of TGF-beta-dependent biological activity as well as NM23-H1 activity.
- Chungbuk National University Korea (Republic of)
Cell Nucleus, Active Transport, Cell Nucleus, RNA-Binding Proteins, Apoptosis, Cell Separation, NM23 Nucleoside Diphosphate Kinases, Recombinant Proteins, Neoplasm Proteins, Protein Structure, Tertiary, Gene Expression Regulation, Neoplastic, Transforming Growth Factor beta, Nucleoside-Diphosphate Kinase, Mutation, Humans, Cysteine, HeLa Cells, Protein Binding
Cell Nucleus, Active Transport, Cell Nucleus, RNA-Binding Proteins, Apoptosis, Cell Separation, NM23 Nucleoside Diphosphate Kinases, Recombinant Proteins, Neoplasm Proteins, Protein Structure, Tertiary, Gene Expression Regulation, Neoplastic, Transforming Growth Factor beta, Nucleoside-Diphosphate Kinase, Mutation, Humans, Cysteine, HeLa Cells, Protein Binding
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