Figure 4

Signal transduction in the Transforming Growth Factor β(TGFβ) family pathway is finely regulated at many levels. Outside the cell latent Transforming Growth Factor β (LTGFβ) is activated by plasmin (uPA) among other unknown extracellular proteases. Thrombospondin-1 and β6 integrin play key roles in assembly and activation of the proteolytic complex. Free TGF β ligand is bound extracellularly and may be sequestered by Decorin. Noggin and Gremlin play similar roles to Decorin, but for Bone Morphogenetic Protein ligands. The TGF β type III receptor (IIIR), also termed betaglycan, presents ligand to the preformed TGF β type I (IR) and type II (IIR) receptor tetrameric signaling complex. This is particularly important with TGFβ 2, where betaglycan substantially increases its binding affinity for the receptor signaling complex. Non Smad signaling pathways activated by ligand binding include Ras-ERK, Rho-JNK, RhoA-p160RCCK, TAK1-p38MAPK and PP2A-S6 kinase. Ligand binding also facilitates phosphorylation and activation of the TGFβ IR serine-threonine kinase domain by the TGFβ IIR serine-threonine kinase domain. TGFβ IR in turn phosphorylates receptor Smads 2/3. The interaction of Smads with the TGFβ IR is facilitated by SARA. BAMBI is a dominant negative, kinase deficient isoform of TGFβ receptor. Smad 7 is an inhibitory Smad that inhibits Smad 2/3 association with Smad4, the co-Smad. Smad7 is a rapidly inducible negative regulator of TGFβ signaling. Phosphorylated receptor Smads 2/3 then associate with the co-Smad4 and translocate to the nucleus, where they coactivate or corepress certain specific target genes by binding to their respective transcription complexes, with or without directly contacting DNA, depending on the promoter in question. Smurf mediate ubiquitination of preformed Smad complexes, thereby negatively regulating Smad signaling to the nucleus. C-Ski and Sno-N are transcriptional factors that negatively regulate Smad activity in the nucleus.