Identification of a structural domain that distinguishes the actions of the type 1 and 2 isoforms of transforming growth factor beta on endothelial cells.
A chimeric transforming growth factor beta (TGF-beta) molecule has been synthesized to map the amino acids responsible for the substantially greater activity of TGF-beta 1 than TGF-beta 2 on growth and migration of endothelial cells. This chimera consists of a dimer of a monomeric unit composed of amino acids 1-39 of TGF-beta 2, 40-82 of TGF-beta 1, and 83-112 of TGF-beta 2. Structural identity of the purified recombinant protein has been confirmed by immunoblotting and NH2-terminal sequencing. The biological potency of the TGF-beta 2-1-2 chimera was equal to that of TGF-beta 1 in inhibition of growth of both fetal bovine heart endothelial cells and rat epididymal fat pad microvascular endothelial cells. Similarly, the TGF-beta 2-1-2 chimera was nearly equivalent to TGF-beta 1 and at least 10-fold more active than TGF-beta 2 in inhibiting migration of bovine aortic endothelial cells. These results identify the sequence between amino acids 40-82 as an important region within TGF-beta that functions to specify a TGF-beta 1- or TGF-beta 2-like activity.
Qian
S W
SW
Laboratory of Chemoprevention, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Burmester
J K
JK
Merwin
J R
JR
Madri
J A
JA
Sporn
M B
MB
Roberts
A B
AB
D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003001:Cloning, Molecular; D004730:Endothelium, Vascular / Q000166:cytology*; D006131:Growth Inhibitors; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D016212:Transforming Growth Factor beta / Q000737:chemistry / Q000494:pharmacology*
D006131:Growth Inhibitors; D009838:Oligodeoxyribonucleotides; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta