INACTIVE TYPE-II AND TYPE-I RECEPTORS FOR TGF-BETA ARE DOMINANT INHIBITORS OF TGF-BETA-DEPENDENT TRANSCRIPTION

被引:56
作者
BRAND, T
SCHNEIDER, MD
机构
[1] BAYLOR COLL MED, DEPT MED, MOLEC CARDIOL UNIT, HOUSTON, TX 77030 USA
[2] BAYLOR COLL MED, DEPT PHYSIOL & MOLEC BIOPHYS, HOUSTON, TX 77030 USA
[3] BAYLOR COLL MED, DEPT CELL BIOL, HOUSTON, TX 77030 USA
关键词
D O I
10.1074/jbc.270.14.8274
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Although transforming growth factor-beta (TGF beta) is implicated in differentiation and disease, proof of in vivo function requires specific inhibitors of the TGF beta cascade. TGF beta binds a family of type I and type II receptors (T beta RI, T beta RII), containing a cytoplasmic serine/threonine kinase domain. We previously reported that kinase-deficient T beta RII (Delta kT beta RII) blocks TGF-beta-dependent transcription in cardiac myocytes. It is controversial whether both receptors are needed in all cells for gene regulation by TGF beta or whether they mediate distinct subsets of TGF-beta-dependent events. To resolve this uncertainty, TGF-beta-dependent transcription was investigated in cardiac myocytes versus mink lung epithelial cells. 1) Delta kT beta RII inhibits induction of a TGF beta-responsive reporter gene, in both cell backgrounds. 2) Charged-to-alanine mutations of key residues of the T beta RII kinase, including consensus ATP binding and amino acid recognition motifs, are competent for binding but not transcriptional activation. Each inactive receptor inhibits TGF beta-dependent transcription in both cell types. 3) Kinase-deficient T beta RI (Delta kT beta RI) likewise impairs TGF beta-dependent transcription, less completely than Delta kT beta RII; kinase-deficient activin type I receptor has no effect. 4) TGF-beta-binding proteins in cardiac cells and Mv1Lu cells are comparable by affinity labeling and immunoprecipitation; however, Mv1Lu cells express up to 3-fold higher levels of T beta RII and T beta RI. Thus, the model inferred from TGF beta-resistant cell lines (that T beta RII and T beta RI are necessary in tandem for the TGF beta-signaling complex to regulate transcription) is valid for cardiac myocytes, the cell type most prominently affected in TGF beta-deficient animals.
引用
收藏
页码:8274 / 8284
页数:11
相关论文
共 69 条
[1]   TGF-BETA RECEPTORS AND ACTIONS [J].
ATTISANO, L ;
WRANA, JL ;
LOPEZCASILLAS, F ;
MASSAGUE, J .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 1994, 1222 (01) :71-80
[2]   CLONING AND DEVELOPMENTAL EXPRESSION OF THE CHICK TYPE-II AND TYPE-III TGF-BETA RECEPTORS [J].
BARNETT, JV ;
MOUSTAKAS, A ;
LIN, W ;
WANG, XF ;
LIN, HY ;
GALPER, JB ;
MAAS, RL .
DEVELOPMENTAL DYNAMICS, 1994, 199 (01) :12-27
[3]   A TRANSFORMING GROWTH-FACTOR-BETA TYPE-I RECEPTOR THAT SIGNALS TO ACTIVATE GENE-EXPRESSION [J].
BASSING, CH ;
YINGLING, JM ;
HOWE, DJ ;
WANG, TW ;
HE, WW ;
GUSTAFSON, ML ;
SHAH, P ;
DONAHOE, PK ;
WANG, XF .
SCIENCE, 1994, 263 (5143) :87-89
[4]  
BASSING CH, 1994, J BIOL CHEM, V269, P14861
[5]  
BRAND T, 1993, J BIOL CHEM, V268, P11500
[6]  
BRANDES ME, 1991, J BIOL CHEM, V266, P19697
[7]   CHARACTERIZATION AND RELATIONSHIP OF DPP RECEPTORS ENCODED BY THE SAXOPHONE AND THICK VEINS GENES IN DROSOPHILA [J].
BRUMMEL, TJ ;
TWOMBLY, V ;
MARQUES, G ;
WRANA, JL ;
NEWFELD, SJ ;
ATTISANO, L ;
MASSAGUE, J ;
OCONNOR, MB ;
GELBART, WM .
CELL, 1994, 78 (02) :251-261
[8]   TYPE-I RECEPTORS SPECIFY GROWTH-INHIBITORY AND TRANSCRIPTIONAL RESPONSES TO TRANSFORMING GROWTH-FACTOR-BETA AND ACTIVIN [J].
CARCAMO, J ;
WEIS, FMB ;
VENTURA, F ;
WIESER, R ;
WRANA, JL ;
ATTISANO, L ;
MASSAGUE, J .
MOLECULAR AND CELLULAR BIOLOGY, 1994, 14 (06) :3810-3821
[9]   A NEU ACQUAINTANCE FOR ERBB3 AND ERBB4 - A ROLE FOR RECEPTOR HETERODIMERIZATION IN GROWTH SIGNALING [J].
CARRAWAY, KL ;
CANTLEY, LC .
CELL, 1994, 78 (01) :5-8
[10]   THE CONSERVED LYSINE OF THE CATALYTIC DOMAIN OF PROTEIN-KINASES IS ACTIVELY INVOLVED IN THE PHOSPHOTRANSFER REACTION AND NOT REQUIRED FOR ANCHORING ATP [J].
CARRERA, AC ;
ALEXANDROV, K ;
ROBERTS, TM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (02) :442-446