TGF Beta Receptors

Abstract

Transforming growth factor-beta 1-3 (TGFβ) are members of a large multifunctional regulatory polypeptide family that controls cellular functions including proliferation, differentiation, migration, apoptosis, adhesion, angiogenesis, immune surveillance, and survival in many cell types. In intact canonical TGFβ signaling, the binding of a TGFβ to the TGFβ type II receptor enables the formation of a heteromeric complex between TGFβ type I and type II receptors. The type I receptor is phosphorylated by the type II receptor serine/threonine kinase. The activated type I receptor phosphorylates receptor-activated Smads that complex with Smad 4. The Smad complexes translocate into the nucleus and regulate target gene transcription through direct or indirect interaction with DNA-binding transcription factors or coactivators. Tumors are resistant to growth inhibition by TGFβ due to inactivation of the TGFβ signaling pathway or aberrant regulation of the cell cycle, in fact, many tumors secrete high levels of TGFβ. TGFβ knockout mice suffer from lethal multifocal inflammatory disease indicating the importance of TGFβ in maintaining immune system homeostasis. TGFβ pathway-directed therapy could reverse the immunosuppressive effects of this cytokine on the host as well as decrease extracellular matrix formation, angiogenesis, and osteolytic activity; and increase the sensitivity of the malignant cells to cytotoxic therapies and immunotherapies.