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

Abstract

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)-β 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 Cys145 of NM23-H1 and Cys152 and Cys270 of STRAP but did not appear to involve Cys4 and Cys109 of NM23-H1, suggesting that a disulfide linkage involving Cys145 of NM23-H1 and Cys152 or Cys270 of STRAP mediates complex formation. The interaction was dependent on the presence of dithiothreitol or β-mercaptoethanol but not H2O2. Ectopic expression of wild-type NM23-H1, but not NM23-H1(C145S), negatively regulated TGF-β signaling in a dose-dependent manner, enhanced stable association between the TGF-β receptor and Smad7, and prevented nuclear translocation of Smad3. Similarly, wild-type NM23-H1 inhibited TGF-β-induced apoptosis and growth inhibition, whereas NM23-H1(C145S) had no effect. Knockdown of NM23-H1 by small interfering RNA stimulated TGF-β 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-β-dependent biological activity as well as NM23-H1 activity. 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)-β 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 Cys145 of NM23-H1 and Cys152 and Cys270 of STRAP but did not appear to involve Cys4 and Cys109 of NM23-H1, suggesting that a disulfide linkage involving Cys145 of NM23-H1 and Cys152 or Cys270 of STRAP mediates complex formation. The interaction was dependent on the presence of dithiothreitol or β-mercaptoethanol but not H2O2. Ectopic expression of wild-type NM23-H1, but not NM23-H1(C145S), negatively regulated TGF-β signaling in a dose-dependent manner, enhanced stable association between the TGF-β receptor and Smad7, and prevented nuclear translocation of Smad3. Similarly, wild-type NM23-H1 inhibited TGF-β-induced apoptosis and growth inhibition, whereas NM23-H1(C145S) had no effect. Knockdown of NM23-H1 by small interfering RNA stimulated TGF-β 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-β-dependent biological activity as well as NM23-H1 activity. The NM23 family of genes is characterized by reduced expression in certain highly metastatic cell lines and tumors (1Steeg P.S. Bevilacqua G. Kopper L. Thorgeirsson U.P. Talmadge J.E. Liotta L.A. Sobel M.E. J. Natl. Cancer Inst. 1988; 80: 200-204Crossref PubMed the NM23 genes that identified to NM23-H1, and or J. PubMed NM23-H1 was identified as a putative metastasis its activity not appear to for its as a metastasis P.S. J. PubMed of NM23 family proteins in for in and J. for is and the of in cell and L. PubMed NM23-H1 and to a in G. G. J. PubMed NM23 the of P.S. J. Natl. Cancer Inst. PubMed The of NM23 family proteins to a of to to modulate by a of growth as transforming growth transforming growth transforming growth STRAP, serine-threonine kinase receptor-associated small interfering transforming growth transforming growth STRAP, serine-threonine kinase receptor-associated small interfering growth growth and growth J. PubMed the of regulation of these signaling by NM23 family proteins is NM23 family proteins to J. PubMed J. PubMed PubMed acid receptor receptor G. PubMed a small J. Natl. PubMed kinase and protein J. PubMed and a receptor G. G. J. PubMed These results suggest that the of of NM23 proteins the regulation and biological of NM23 family STRAP protein and TGF-β Through STRAP and negatively TGF-β signaling by the association between TGF-β receptor and J. PubMed PubMed we that the association of NM23-H1 STRAP in is important for the regulation of signaling as well as NM23-H1 activity. and and in as J. PubMed and and J. PubMed and in and and dithiothreitol and was and NM23-H1 mutants by the a NM23-H1 was as the for the or in of the in the of for NM23-H1 Cys4 for NM23-H1 Cys109 for NM23-H1 Cys145 The and The by the and to a of in the of the of was and and the and proteins of NM23-H1 and and of in was the of to proteins of NM23-H1 of STRAP was the and the in the of STRAP for STRAP Cys152 for STRAP Cys270 the substitution of STRAP was as the and the and for the STRAP and was STRAP, and as The for and and a The for and by of The was a J. Cancer The and by and STRAP J. PubMed screen for the of NM23-H1-interacting proteins was as J. PubMed in and or the expression to the as J. PubMed the was the as that of that did not or and not to to two amino amino of NM23-H1, and a J. Cancer PubMed The and for as J. PubMed or HaCaT in the the of the by to of of or STRAP and the C270S, and and NM23-H1 and the C109S, and by the of NM23-H1 and STRAP and by or a as J. PubMed the of on a the and The protein was a of in a the or the expression and activity was a to the and as J. PubMed for apoptosis as J. PubMed on expression protein the expression the for for for and and The a and a as J. PubMed The of was by the of and by the of cells. of the of expression STRAP, wild-type NM23-H1, and and and in of by and the was on for and for The was the by in of and on for The was for and the was in a and of of NM23-H1, of wild-type or NM23-H1 for in a The was by the of of and for by and the was to the activity of NM23-H1, of of for in a of of The a to a of of the wild-type or NM23-H1 in a of of for The was by the of of for and by The was to of NM23-H1 kinase was in as P.S. J. PubMed of wild-type or NM23-H1 and in in a of for The was by the of of The was and by in The and to and the of was by the expression or or and for to the in was for in the presence or of as and for a and was a and the the was as J. PubMed on the expression The on and and for and in or in was for The and or for The and on proteins on a NM23-H1 STRAP in proteins that NM23-H1, we a screen the NM23-H1 as a as J. PubMed of a to the of not was to STRAP, a TGF-β receptor-interacting protein J. PubMed on we NM23-H1 STRAP in by a of and expression was in association NM23-H1 These the results of the screen and demonstrated that NM23-H1 STRAP in cells. the association between NM23-H1 and STRAP, we a of proteins or as a NM23-H1 was in cell lines and J. PubMed that NM23-H1 STRAP in the of NM23-H1 and STRAP, was expression and STRAP and NM23-H1 in the and as in the in These results that NM23-H1 and STRAP in of NM23-H1 and STRAP in by disulfide as well as protein in the proteins J. PubMed STRAP J. PubMed NM23-H1 of the protein that potentially its interaction the of that the interaction of NM23-H1 and STRAP is by cysteine in the two expression or the NM23-H1 substitution mutants and NM23-H1(C145S), expression for wild-type STRAP was and complex between NM23-H1 and STRAP was by was a in complex in NM23-H1(C145S), wild-type NM23-H1, whereas complex was not in and These results that Cys145 of NM23-H1 a in the association of NM23-H1 The of STRAP and NM23-H1 in was and that the in complex was not to in STRAP and NM23-H1 expression The of STRAP that in and the of PubMed cysteine the of STRAP and complex between NM23-H1 and STRAP, expression wild-type and of and Coexpression of NM23-H1(C145S) STRAP or in a in complex between NM23-H1 and STRAP and whereas of wild-type NM23-H1 STRAP or in a in complex as the expression of wild-type NM23-H1 and wild-type STRAP and These results that Cys152 and Cys270 of STRAP important in its association of Cys270 of STRAP, is the had a on complex of is the and and the of Cys152 and Cys270 of STRAP in its association NM23-H1, we a substitution of STRAP, STRAP(C152S/C270S), and its in the in of STRAP inhibited complex between NM23-H1 and STRAP and these results that cysteine Cys152 and Cys270 of STRAP and Cys145 of NM23-H1, a in the association of NM23-H1 and STRAP in the interaction of NM23-H1 and STRAP was we complex in in The presence of the and β-mercaptoethanol the of STRAP that NM23-H1, whereas the had no These results that the in association of NM23-H1 STRAP is dependent on the of the two the association of NM23-H1 and STRAP NM23-H1 was to and in a in the of NM23-H1 was in the presence of wild-type STRAP but was NM23-H1 was in the of STRAP of a association between NM23-H1 and The was not NM23-H1 was these results that complex between NM23-H1 and STRAP cysteine in of the two of the NM23-H1 of the STRAP for its association NM23-H1, we a of STRAP mutants and to NM23-H1 in in NM23-H1 the but not the These results that the interaction of STRAP NM23-H1 is the of the of STRAP, we the of STRAP and The of NM23-H1 to and was whereas NM23-H1 to and was was in the that Cys152 and Cys270 of STRAP a in its association cysteine STRAP, and to no in the association between NM23-H1 and STRAP and these results demonstrated that STRAP to NM23-H1 the and the of STRAP in NM23-H1 of wild-type STRAP and STRAP the of wild-type STRAP the of the to and the The amino acid and the amino to the and cysteine and the of wild-type and and of the NM23-H1 of expression or expression for or to and protein by The was and to the of proteins in the the of expression of STRAP was by The of of NM23-H1 and STRAP by that NM23-H1 and in and in as well as of and J. PubMed J. J. PubMed G. J. PubMed G. J. PubMed J. 1988; PubMed J. PubMed PubMed of these we in the of the cysteine of NM23-H1 in complex between NM23-H1 and NM23-H1 or between NM23-H1 and The expression of the NM23-H1 mutants and NM23-H1(C145S) had no on complex between NM23-H1 and NM23-H1 or NM23-H1 and suggesting that the in these proteins not the of NM23-H1 that is for that the of NM23-H1 not its we of STRAP complex between NM23-H1 and NM23-H1 or between NM23-H1 and did not in complex between NM23-H1 and NM23-H1 or NM23-H1 and in the presence of STRAP, in to the association of NM23-H1 and STRAP, of NM23-H1 or of NM23-H1 not to the of the wild-type and of NM23-H1 and The results that the of and NM23-H1(C145S) and of and that of wild-type NM23-H1 and wild-type STRAP, and that the of of the NM23-H1 and STRAP as by not by the the of STRAP the of STRAP PubMed in no in the of STRAP in the presence of the STRAP These results that the of STRAP not its to and no on the of that STRAP the TGF-β receptor PubMed J. PubMed the STRAP substitution mutants could the TGF-β expression for wild-type and of STRAP, a protein of a of the TGF-β and protein by of STRAP in to wild-type STRAP, the STRAP mutants the TGF-β These results that the of STRAP is not by the these that NM23-H1 STRAP disulfide involving cysteine and that the of NM23-H1 and STRAP not the of these of the on the of NM23-H1 and and of of NM23-H1 on the association between NM23-H1 and NM23-H1 or between NM23-H1 and expression the proteins on and proteins by was by The was and to the of of protein the expression of proteins by of STRAP on the association between NM23-H1 and NM23-H1 or between NM23-H1 and the of expression for and and cell to between NM23-H1 and NM23-H1 or between NM23-H1 and was by The of NM23-H1 and and STRAP and NM23-H1 in by the and of and the of NM23-H1, as well as and the of protein was a of in of of STRAP on its expression the and proteins on and by The of STRAP was by of of STRAP on the association between TGF-β receptor and expression the and in as for The was and to the of of the expression of by The of of the on the of NM23-H1 and and of of NM23-H1 on the association between NM23-H1 and NM23-H1 or between NM23-H1 and expression the proteins on and proteins by was by The was and to the of of protein the expression of proteins by of STRAP on the association between NM23-H1 and NM23-H1 or between NM23-H1 and the of expression for and and cell to between NM23-H1 and NM23-H1 or between NM23-H1 and was by The of NM23-H1 and and STRAP and NM23-H1 in by the and of and the of NM23-H1, as well as and the of protein was a of in of of STRAP on its expression the and proteins on and by The of STRAP was by of of STRAP on the association between TGF-β receptor and expression the and in as for The was and to the of of the expression of by The of of of NM23-H1 and STRAP of activity expression of STRAP is a well for the biological activity of STRAP J. PubMed the STRAP mutants activity expression for wild-type and of STRAP, was the and its activity was in in kinase and kinase as a PubMed to wild-type STRAP, of STRAP mutants in a in activity that the of STRAP not the of STRAP to activity. that NM23-H1 of and kinase activity J. PubMed the of NM23-H1 its we the and kinase of wild-type and of The of the substitution mutants to of wild-type NM23-H1 in that the of NM23-H1 not modulate its these results that the of NM23-H1 and STRAP not the of these NM23-H1 TGF-β-induced that STRAP as a or and negatively TGF-β-induced in a dose-dependent PubMed the of the interaction of NM23-H1 and STRAP, we the of NM23-H1 expression on TGF-β-induced and to STRAP J. PubMed of NM23-H1 in TGF-β-induced activity in a dose-dependent the interaction of NM23-H1 STRAP TGF-β-induced of NM23-H1 STRAP enhanced the of in a dose-dependent manner, as the of expression of STRAP suggesting that NM23-H1 and STRAP in the of TGF-β signaling. STRAP is for NM23-H1-induced of TGF-β we that in of STRAP in a in TGF-β-induced and the was to the of in the was on TGF-β signaling expression of NM23-H1 in STRAP that the direct interaction between NM23-H1 and STRAP important in NM23-H1-induced of TGF-β signaling. the of TGF-β-induced by NM23-H1 is or dependent on its interaction STRAP, we the of expression of the NM23-H1 substitution mutants on TGF-β-induced in expression of NM23-H1(C145S) did not TGF-β-induced whereas expression of wild-type NM23-H1, and significantly TGF-β-induced to a in a dose-dependent Cys145 of NM23-H1 is in the association STRAP that the direct interaction between NM23-H1 and STRAP important in the of TGF-β signaling. of NM23-H1 two and in of NM23-H1, but not a in a of TGF-β-induced and the was to the of in the that the of NM23-H1 was significantly reduced in NM23-H1 or the These results that of NM23-H1 TGF-β-induced to of the of stable expression of NM23-H1 on signaling NM23-H1 and gene expression in these in to TGF-β signaling by a of TGF-β of NM23-H1 of and and the of and proteins genes and by TGF-β the of stable expression of NM23-H1 on TGF-β we NM23-H1 and for TGF-β-induced gene of NM23-H1 significantly the expression of and and the expression and results in the results we the stable and these that NM23-H1 STRAP and of TGF-β of of TGF-β signaling by of of of of expression for as and of expression for the NM23-H1 proteins in the presence or of STRAP and stimulated by regulation of TGF-β-induced by of and and of or of as in the presence or of The of a the expression of STRAP was by of of STRAP expression and of expression wild-type and NM23-H1 proteins and stimulated by activity was and to activity. The to STRAP is The The of of TGF-β-induced by of and of the and as The to that did not is The of a expression of NM23-H1 and by and and of NM23-H1 on the expression of TGF-β NM23-H1 and and to and of the TGF-β was to TGF-β signaling of TGF-β genes by as and for to and of protein in by The of of of TGF-β signaling by of of of of expression for as and of expression for the NM23-H1 proteins in the presence or of STRAP and stimulated by regulation of TGF-β-induced by of and and of or of as in the presence or of The of a the expression of STRAP was by of of STRAP expression and of expression wild-type and NM23-H1 proteins and stimulated by activity was and to activity. The to STRAP is The The of of TGF-β-induced by of and of the and as The to that did not is The of a expression of NM23-H1 and by and and of NM23-H1 on the expression of TGF-β NM23-H1 and and to and of the TGF-β was to TGF-β signaling of TGF-β genes by as and for to and of protein in by The of NM23-H1 in the of TGF-β-induced and to a signaling that is for cell cell and protein and to negatively TGF-β-induced J. PubMed PubMed NM23-H1 to TGF-β-induced we NM23-H1 was in TGF-β-induced and HaCaT expression NM23-H1, and STRAP, and apoptosis was in the presence or of TGF-β by for in nuclear as and NM23-H1 and STRAP a of of apoptosis NM23-H1 or STRAP and these expression of STRAP had a on the of TGF-β-induced apoptosis NM23-H1 The of NM23-H1 on TGF-β-induced apoptosis was cell was significantly by in a dose-dependent that NM23-H1, STRAP, cell the of TGF-β-induced signaling. that NM23-H1 important in the regulation of TGF-β-induced we of wild-type and NM23-H1(C145S) and the on TGF-β-induced apoptosis to STRAP PubMed the of wild-type NM23-H1 to TGF-β-induced apoptosis was dose-dependent and expression of NM23-H1(C145S) had no on TGF-β-induced apoptosis and the results of the These results that the Cys145 of NM23-H1 a in the regulation of TGF-β-induced by a direct interaction of NM23-H1 on TGF-β-induced apoptosis and growth of NM23-H1 on TGF-β-induced or HaCaT expression NM23-H1 STRAP expression as and or HaCaT for and for to for the presence of of on TGF-β-induced or HaCaT expression and or HaCaT for and as for to the of and of of wild-type NM23-H1 or NM23-H1(C145S) on of TGF-β-induced or HaCaT and of expression for wild-type or NM23-H1(C145S), as in the presence or of of STRAP expression expression for to and apoptosis was as for of STRAP and NM23-H1 by and of NM23-H1 or the on of TGF-β-induced growth HaCaT a or expression for STRAP, or in by for or for in the or presence of The of in and was by The of in was and is in the the of on of TGF-β-induced growth HaCaT the or expression for STRAP, in by as for or for in the or presence of and the of in and was by The of in was and is in the the the of and of of NM23-H1 on TGF-β-induced apoptosis and growth of NM23-H1 on TGF-β-induced or HaCaT expression NM23-H1 STRAP expression as and or HaCaT for and for to for the presence of of on TGF-β-induced or HaCaT expression and or HaCaT for and as for to the of and of of wild-type NM23-H1 or NM23-H1(C145S) on of TGF-β-induced or HaCaT and of expression for wild-type or NM23-H1(C145S), as in the presence or of of STRAP expression expression for to and apoptosis was as for of STRAP and NM23-H1 by and of NM23-H1 or the on of TGF-β-induced growth HaCaT a or expression for STRAP, or in by for or for in the or presence of The of in and was by The of in was and is in the the of on of TGF-β-induced growth HaCaT the or expression for STRAP, in by as for or for in the or presence of and the of in and was by The of in was and is in the the the of and of the of the association between NM23-H1 and STRAP, we the of wild-type NM23-H1 and NM23-H1(C145S) on TGF-β-induced growth in of HaCaT STRAP in of in the presence of TGF-β in the of TGF-β in the presence of a of in STRAP was wild-type NM23-H1 the expression of STRAP Coexpression of NM23-H1(C145S) had no was no in the of in between STRAP and STRAP NM23-H1(C145S) in the presence of TGF-β of cell in the presence of TGF-β is in the in These results that Cys145 of NM23-H1 important in the regulation of growth in to HaCaT by in the of NM23-H1 by NM23-H1 in a in the of in for a of NM23-H1 in the regulation of growth in to of cell these is in the in these results that NM23-H1 is in the regulation of TGF-β-induced apoptosis and growth of TGF-β signaling. NM23-H1 the of that STRAP TGF-β signaling by the complex of TGF-β receptor and PubMed the of of TGF-β we NM23-H1, STRAP, the interaction between TGF-β receptor and in in expression Smad7, STRAP, and NM23-H1, and the on complex was by in the association between and was significantly expression of of wild-type NM23-H1, as that did not NM23-H1 we the of NM23-H1(C145S), is to STRAP, we that expression of NM23-H1(C145S) had no on the association between and that the association between NM23-H1 and STRAP is important for the complex and TGF-β signaling. expression of NM23-H1 the association between STRAP and Smad7, STRAP, in Smad7, to in and to the TGF-β receptor PubMed in the interaction of STRAP was of wild-type NM23-H1, that did not NM23-H1, and was dependent on the of NM23-H1 expression in the and that NM23-H1 negatively TGF-β signaling by in the of to the TGF-β receptor by was no on the association between STRAP and in NM23-H1(C145S) and in the a in TGF-β signaling. NM23-H1 translocation the of expression NM23-H1 and as in the presence or of in in the of and TGF-β was in nuclear translocation Coexpression of NM23-H1 inhibited the TGF-β-induced nuclear translocation of did not in NM23-H1 expression of in the presence or of TGF-β of nuclear we the of in NM23-H1(C145S), and STRAP in in the presence of expression of NM23-H1(C145S) had the of wild-type the of the interaction between NM23-H1 and STRAP in the regulation of TGF-β signaling. of and nuclear of cell to the of in the presence or of wild-type NM23-H1 or the presence of in the nuclear of and was significantly expression of wild-type NM23-H1 was a in the of in the the and was in the of between and NM23-H1(C145S) these results that expression of NM23-H1 the translocation of the to the in to nuclear translocation of Smad3. and of NM23-H1 on the association of TGF-β receptor and and STRAP and the of expression for Smad7, and STRAP of wild-type NM23-H1 or NM23-H1(C145S) and or the of expression for STRAP and of wild-type NM23-H1 or NM23-H1(C145S) and was by as for and of by the of expression for and NM23-H1 in the presence or of or by or NM23-H1, and by of NM23-H1(C145S) on the of expression for STRAP, wild-type NM23-H1, and NM23-H1(C145S) in the presence or of by and by was by and nuclear of the expression in the presence of by the and the and nuclear of the was by The of expression was and the to that did not NM23-H1 is The of nuclear translocation of Smad3. and of NM23-H1 on the association of TGF-β receptor and and STRAP and the of expression for Smad7, and STRAP of wild-type NM23-H1 or NM23-H1(C145S) and or the of expression for STRAP and of wild-type NM23-H1 or NM23-H1(C145S) and was by as for and of by the of expression for and NM23-H1 in the presence or of or by or NM23-H1, and by of NM23-H1(C145S) on the of expression for STRAP, wild-type NM23-H1, and NM23-H1(C145S) in the presence or of by and by was by and nuclear of the expression in the presence of by the and the and nuclear of the was by The of expression was and the to that did not NM23-H1 is The of STRAP NM23-H1-induced of NM23-H1 in cell growth and demonstrated in cell J. J. PubMed NM23-H1 was in the regulation of cell growth in HaCaT we a of cell growth that the expression of NM23-H1 in HaCaT to of cell growth in a dose-dependent manner, as demonstrated by the of in not that HaCaT as a for the regulation of cell growth by HaCaT and a or expression NM23-H1, or and by HaCaT NM23-H1 HaCaT NM23-H1 and STRAP had a significantly of in of NM23-H1 and that STRAP NM23-H1 in the of NM23-H1-induced cell Coexpression of had on NM23-H1-induced cell growth NM23-H1 and was by of the of in in the presence of these results that Cys152 and Cys270 of STRAP important in the regulation of NM23-H1-induced cell by the interaction between STRAP and NM23 family proteins in a of biological and J. to the of of NM23 and proteins J. PubMed The NM23 genes identified to L. J. PubMed NM23 proteins activity for the of proteins J. PubMed that NM23-H1 a complex in and that of complex is important for the protein activity of NM23-H1 J. PubMed J. PubMed that and activity identified in NM23 family NM23-H1, and NM23 J. PubMed Natl. PubMed Natl. PubMed NM23-H1 or of NM23-H1 and J. PubMed J. J. PubMed G. J. PubMed G. J. PubMed J. 1988; PubMed J. PubMed PubMed The of NM23-H1 to by is and was that disulfide and of NM23-H1 is by Cys109 of NM23-H1 and that the kinase activity of a substitution of NM23-H1 is to wild-type NM23-H1 PubMed suggesting the of disulfide between NM23-H1 and its NM23 family proteins to proteins G. G. J. PubMed J. PubMed J. PubMed PubMed G. PubMed J. Natl. PubMed J. PubMed these we for of NM23-H1 in to the of regulation of the of NM23 family we identified and characterized STRAP as a of STRAP was as a TGF-β receptor-interacting protein. The association of STRAP a on the of TGF-β signaling by these proteins PubMed J. PubMed that STRAP as and TGF-β signaling J. PubMed that expression of STRAP significantly kinase suggesting that STRAP to the of its on these the association of STRAP NM23-H1 of regulation of NM23-H1 activity and TGF-β signaling. the we demonstrated that of significantly inhibited and kinase activity not as well as NM23-H1-induced cell These results the of the interaction between STRAP and in and in not two cysteine and the of STRAP that in the direct interaction between STRAP and NM23-H1 in the regulation of the and biological of NM23-H1, suggesting that the direct interaction between these two proteins important in the of NM23-H1 activity. suggest that NM23 family proteins in P.S. Cancer G. is that the regulation of biological as and by NM23 proteins to modulate the signaling that these J. PubMed the by signaling by NM23-H1 is to putative of regulation of NM23 family we a screen NM23-H1 as a and identified STRAP as NM23-H1-interacting protein. the in we demonstrated that in we that the interaction of NM23-H1 STRAP to of the of STRAP on signaling suggesting that NM23-H1 as a of TGF-β signaling direct to we the that proteins that STRAP could the of TGF-β we demonstrated that STRAP of TGF-β signaling J. PubMed that of the amino acid substitution mutants of NM23-H1, the of NM23-H1(C145S), significantly enhanced of TGF-β signaling that the direct interaction between NM23-H1 and STRAP, disulfide of cysteine a in the regulation of TGF-β signaling. is the of NM23-H1(C145S) expression on apoptosis and growth identified a putative of of TGF-β signaling by NM23-H1, that of wild-type NM23-H1, but not NM23-H1(C145S), significantly the interaction between TGF-β receptor and in a dose-dependent These results that wild-type NM23-H1, J. PubMed to the of TGF-β in TGF-β signaling. the results of the that NM23-H1 STRAP in and that complex the of cysteine of NM23-H1 and STRAP, complex of the of the association between NM23-H1 and STRAP, a for the complex in of apoptosis and growth inhibition, of the of NM23-H1, and kinase not as well as NM23-H1-induced cell results to a of regulation of TGF-β signaling and biological