Mechanisms in TGF-beta action.
The various isoforms of TGF-beta are multifunctional. We are exploring pathways of cellular regulation by TGF-beta that lead to suppression of cell proliferation, modulation of cell adhesion and control of cell differentiation. These cellular responses appear to be activated by binding of TGF-beta to a similar set of receptor glycoproteins in all cell types. TGF-beta receptor types I and II are specifically lost in cell mutants that are resistant to TGF-beta. The concomitant loss of these two receptors in certain mutants suggests that they are components of the TGF-beta signal-transducing receptor complex. Inhibition of epithelial cell proliferation by TGF-beta is linked to retention of the retinoblastoma growth suppressor gene product in an underphosphorylated state that is presumed to have growth suppressive activity. Inhibition of myogenic differentiation by TGF-beta involves a block in the expression of the master myogenic differentiation genes, such as myogenin, but appears also to involve up-regulation of extracellular matrix production. Expression of components of the cell adhesion apparatus--cell adhesion receptors and extracellular matrix proteins--is controlled by TGF-beta in an array of cell types. This response could have a great impact on the ability of cells to migrate, home to specific tissue locations and differentiate during development, invasion and metastasis.
Massagué
J
J
Howard Hughes Medical Institute, New York, NY.
Heino
J
J
Laiho
M
M
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002642:Chick Embryo; D004847:Epithelial Cells; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D016023:Integrins / Q000096:biosynthesis; D051379:Mice; D009124:Muscle Proteins / Q000096:biosynthesis; D009132:Muscles / Q000166:cytology; D017570:MyoD Protein; D018008:Myogenin; D009687:Nuclear Proteins / Q000096:biosynthesis; D010750:Phosphoproteins / Q000096:biosynthesis; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology; D018125:Receptors, Transforming Growth Factor beta; D016160:Retinoblastoma Protein / Q000502:physiology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology*
D016326:Extracellular Matrix Proteins; D016023:Integrins; D009124:Muscle Proteins; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C503801:Myog protein, mouse; C503803:Myog protein, rat; D018008:Myogenin; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta