All tags Cancer TGF-beta/SMAD pathway

TGF-beta/SMAD pathway

The transforming growth factor-β (TGFβ) proteins are cytokines that are critical during development and homeostasis of somatic tissue.

They have been shown to orchestrate a number of cellular processes, including cell growth, differentiation, cell migration, invasion and extracellular matrix remodeling. The TGFβ family is broadly divided into two sub-families, TGFβ ligands and bone morphogenic protein (BMP) ligands, on the basis of their homology, receptor binding and SMAD activation.

TGFβ signaling is induced by ligand binding to its cognate cell membrane receptors, which are serine/threonine protein kinases. The cell membrane receptors are classed as type I or II receptors. The type II receptors are constitutively active. Upon ligand binding, they are brought into close proximity to type I receptors to phosphorylate and activate them.

The canonical signaling pathway

In canonical signaling, receptor activation induces the C-terminal phosphorylation of a group of transcription factors (TFs) known as SMADs. The phosphorylated SMADs then form a complex with a co-mediator SMADSMAD4, that is translocated to the nucleus where it binds to gene promoters. In co-operation with different TFs and co-factors, these complexes control the transcription of hundreds of genes. The SMADs also activate transcription of genes encoding the inhibitory SMADsSMAD6 and 7, initiating a negative feedback loop to inhibit signaling.

Non-canonical signaling refers to the activation of other signaling pathways after TGFβ receptor ligation. These include the  MAPK (ERKp38 and JNK), PI3K/Akt and Rho GTPase pathways.

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