Transforming Growth Factor-β Signaling

Members of the transforming growth factor β (TGF-β) family regulate cell proliferation, migration, and differentiation during embryonal development and in tissue homeostasis in the adult. They signal by inducing heteromeric complexes of type I and type II serine/threonine kinase receptors. Ligand binding activates the type I receptor kinase leading to phosphorylation of members of the Smad family, which after oligomerization are translocated to the nucleus where they together with other nuclear factors regulate the transcription of specific genes. TGF-β family members also signal via non-Smad pathways, including Erk, JNK, and p38 MAP-kinase pathways, the tyrosine kinase Src, the small GTPase Rho, and cleavage of the type I receptor whereby the intracellular domain is translocated to the nucleus where it drives an invasiveness program. The TGF-β signaling pathways are carefully regulated by posttranslational mechanisms, including phosphorylation, ubiquitination, acetylation, sumoylation, and PAR-ylation, as well as by positive and negative feedback mechanisms and cross talk with other signaling pathways.