Open AccessCharacterization of distinct functional domains of transforming growth factor beta.
Author(s) -
James K. Burmester,
Su Wen Qian,
Anita B. Roberts,
Alison Huang,
Supavadee Amatayakul-Chantler,
L. Suardet,
N Odartchenko,
Joseph A. Madri,
Michael B. Sporn
Publication year - 1993
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.90.18.8628
Subject(s) - gene isoform , transforming growth factor beta , beta (programming language) , tgf beta signaling pathway , biology , transforming growth factor , amino acid , transforming growth factor, beta 3 , cell culture , microbiology and biotechnology , chemistry , tgf alpha , biochemistry , growth factor , gene , receptor , genetics , computer science , programming language
Three distinct isoforms of transforming growth factor beta (TGF-beta) are expressed in mammalian cells. Although many cells respond equivalently to all three isoforms, certain cells respond selectively. Using chimeric proteins in which selected regions of the different isoforms were interchanged, we have identified two distinct functional domains of TGF-beta involved in determining the biological potencies and functions of the molecule. The first domain is important for determining whether TGF-beta can be sequestered by alpha 2-macroglobulin. By replacing aa 45 and 47 of TGF-beta 2 with the corresponding amino acids of TGF-beta 1, sequestration of the TGF-beta molecule by alpha 2-macroglobulin was markedly reduced. The second domain is functionally different from the alpha 2-macroglobulin sequestration site and is important for determining the potency of TGF-beta to inhibit growth of the LS513 human colorectal cancer cell line. Neither the TGF-beta 2/beta 1-(40-47) replacement construct nor a chimera containing aa 1-39 of TGF-beta 2, aa 40-82 of TGF-beta 1, and aa 83-112 of TGF-beta 2 was equivalent to TGF-beta 1 in inhibiting growth of LS513 cells. This fact suggests that additional amino acids outside of the aa 40-82 region are required to specify TGF-beta 1 activity with these cells.