The multiple TGFβ signaling pathways. The canonical Smad pathway is responsible for most of the TGFβ biological responses leading to tumor suppression (growth arrest, apoptosis, and prevention of immortalization) and tumor promotion (EMT, migration, invasion, and metastasis). Even though Smads are central to TGFβ signaling, ligands from this family also signal through other non-Smad pathways. As indicated, TGFβ can activate the PI3 K/Akt, RhoGTPase, MAPK, and stress-activated kinase (p38/JNK) pathways, leading to various biological effects. Depicted by the orange arrows, these pathways also cross-talk or synergise with the Smad pathway to antagonize or potentiate TGFβ signaling, respectively. Several Smad inhibitory pathways are also indicated, including TGFβ-induced gene expression of the inhibitory Smad7, and R-Smad linker phosphorylation by intracellular protein kinases (GRK2, CDK4, PKC, CamKII, MAPK, and Casein kinase).