Inactivation of the Type II Receptor Reveals Two Receptor Pathways for the Diverse TGF-β Activities

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Abstract
Transforming growth factor-beta (TGF-beta) is a multifunctional protein that regulates cell proliferation and differentiation and extracellular matrix production. Although two receptor types, the type I and type II receptors, have been implicated in TGF-beta-induced signaling, it is unclear how the many activities of TGF-beta are mediated through these receptors. With the use of cells overexpressing truncated type II receptors as dominant negative mutants to selectively block type II receptor signaling, the existence of two receptor pathways was shown. The type II receptors, possibly in conjunction with type I receptors, mediate the induction of growth inhibition and hypophosphorylation of the retinoblastoma gene product pRB. The type I receptors are responsible for effects on extracellular matrix, such as the induction of fibronectin and plasminogen activator inhibitor I, and for increased JunB expression. Selective inactivation of the type II receptors alters the TGF-beta response in a similar manner to the functional inactivation of pRB, suggesting a role for pRB in the type II, but not the type I, receptor pathway.