IndraLab

"from Figure 1 - Fig 1. The transforming growth factor beta (TGF-b) signaling pathway. TGF-b binds type II TGF-b receptor (TbRII), directly or through TbRIII, inducing association of TbRII with TbRI. TbRII then phosphorylates and activates TbRI, which then phosphorylates Smad2 or Smad3. Phosphorylated Smad2 or Smad3 associates with Smad4 and they translocate into the nucleus, where they activate transcription of target genes. Smad7 inhibits TGF-b signaling by preventing the activation of Smad2 or Smad3 by TbRI."

"TGF-beta-mediated activation of TGF-beta type I receptor stimulates the phosphorylation of Smad2 and Smad3 and subsequent heteromeric complex formation with Smad4."

"TGF-B1 is the most abundant and universally expressed isoform; most studies have either examined or been performed with exogenous TGF-B1. TGF-B is secreted into the extracellular matrix as a latent protein complex bound to a latency- associated protein and one of the four isoforms of latent TGF-B binding protein. Activation of TGF-B, which is required for biologic activity, occurs through poorly understood mechanisms likely involving proteolytic processing of the associated proteins and release of the TGF-B ligand. Once activated, the TGF-B ligands regulate cellular processes by binding to three high-affinity cell surface receptors: the type I TGF-B receptor (TBRI), type II TGF-B receptor (TBRII), and type III TGF-B receptor (TBRIII, also referred to as betaglycan). Where expressed, TBRIII is the most abundant TGF-B receptor and classically functions by binding the TGF-B ligand and transferring it to its signaling receptors, TBRI and TBRII.12 TBRI and TBRII contain serine/threonine protein kinases in their intracellular domains. TBRI initiates intracellular signaling by phosphorylating a family of transcription factors, the Smads. Smad2 and Smad3 are the receptor-activated Smads for TGF-B because they are phosphorylated by TBRI. Smad4 is a common partner for all of the receptor-activated Smads. Smad6 and Smad7 are inhibitory Smads that block the phosphorylation of Smad2 or Smad3, thus inhibiting TGF-B signaling. A general mechanism for TGF-B signaling has been elucidated (Fig 1).13,14 The TGF-B ligand either binds to TBRIII, which presents TGF-B to TBRII, or binds to TBRII directly. Once bound to TGF-B, TBRII recruits, binds, and transphosphorylates TBRI, thereby stimulating its protein kinase activity. The activated TBRI phosphorylates Smad2 or Smad3, which binds to Smad4. The resulting Smad complex translocates into the nucleus and interacts in a cell specific manner with transcription factors to regulate specifically the transcription of a multitude of TGF-B responsive genes"

"Activin receptor-like kinase-1 (ALK1) induces Smad1/5 phosphorylation, leading to an increase in endothelial cell proliferation and migration, while ALK5 promotes Smad2/3 activation and inhibits both processes."