A portrait of Transforming Growth Factor β superfamily signalling: Background matters

Ligands of the Transforming Growth Factor β superfamily like Transforming Growth Factor β and Bone Morphogenetic Proteins govern developmental processes and regulate adult homeostasis by controlling cellular proliferation, survival, differentiation and migration. Aberrant signalling activity is associated with human disorders such as cancer, cardiovascular, musculoskeletal, or fibrotic disease. Upon binding to specific sets of cognate cell surface receptors, family members induce highly similar pathways which include canonical SMAD dependent signalling as well as pathways without direct involvement of SMAD proteins, which activate signalling molecules like mitogen-activated protein kinases or small GTPases. The diverse ligand functionalities are achieved through regulation and modulation of the pathways at all levels, resulting in a highly quantitative and context sensitive signal integration reflecting the cellular state and background. Strategies to target Transforming Growth Factor β or Bone Morphogenetic Protein pathways have been developed on the basis of our current understanding and have proven a highly beneficial potential.