TGF-beta signaling controls a plethora of cellular responses and figures prominently in animal development. Recent cellular, biochemical, and structural studies have revealed significant insight into the mechanisms of the activation of TGF-beta receptors through ligand binding, the activation of Smad proteins through phosphorylation, the transcriptional regulation of target gene expression, and the control of Smad protein activity and degradation. This article reviews these latest advances and presents our current understanding on the mechanisms of TGF-beta signaling from cell membrane to the nucleus.

The transforming growth factor β (TGF-β) family of growth factors control the development and homeostasis of most tissues in metazoan organisms. Work over the past few years has led to the elucidation of a TGF-β signal transduction network. This network involves receptor serine/threonine kinases at the cell surface and their substrates, the SMAD proteins, which move into the nucleus, where they activate target gene transcription in association with DNA-binding partners. Distinct repertoires of receptors, SMAD proteins, and DNA-binding partners seemingly underlie, in a cell-specific manner, the multifunctional nature of TGF-β and related factors. Mutations in these pathways are the cause of various forms of human cancer and developmental disorders. CONTENTS

The transforming growth factor β (TGFβ) signaling pathway is a key player in metazoan biology, and its misregulation can result in tumor development. The regulatory cytokine TGFβ exerts tumor-suppressive effects that cancer cells must elude for malignant evolution. Yet, paradoxically, TGFβ also modulates processes such as cell invasion, immune regulation, and microenvironment modification that cancer cells may exploit to their advantage. Consequently, the output of a TGFβ response is highly contextual throughout development, across different tissues, and also in cancer. The mechanistic basis and clinical relevance of TGFβ’s role in cancer is becoming increasingly clear, paving the way for a better understanding of the complexity and therapeutic potential of this pathway.