[PDF][PDF] Targeting the TGFβ signaling network in human neoplasia

N Dumont, CL Arteaga - Cancer cell, 2003 - cell.com
N Dumont, CL Arteaga
Cancer cell, 2003cell.com
The transforming growth factor (TGF) βs are polypeptides within a superfamily of ligands that
includes the TGFβs, activins, and bone morphogenetic proteins (BMPs). TGFβ ligands play a
role in cell proliferation, functional differentiation, extracellular matrix (ECM) production, cell
motility, and apoptosis (Massagué, 1998). Three mammalian TGFβ isoforms, TGFβ1, TGFβ2,
and TGFβ3, have been identified. In general, they exhibit similar functions in vitro, most
notably on cell growth regulation, ECM production, and immune modulation. However, each …
The transforming growth factor (TGF) βs are polypeptides within a superfamily of ligands that includes the TGFβs, activins, and bone morphogenetic proteins (BMPs). TGFβ ligands play a role in cell proliferation, functional differentiation, extracellular matrix (ECM) production, cell motility, and apoptosis (Massagué, 1998). Three mammalian TGFβ isoforms, TGFβ1, TGFβ2, and TGFβ3, have been identified. In general, they exhibit similar functions in vitro, most notably on cell growth regulation, ECM production, and immune modulation. However, each appears to have distinct activities in vivo, as evidenced by the distinct phenotypes of mice lacking any one of the TGFβ ligands (Massagué, 1998). The TGFβs bind to a heteromeric complex of transmembrane serine/threonine kinases, the type I and type II receptors (TβRI and TβRII). Following ligand binding to TβRII, TβRI is recruited to the complex. This allows for the constitutively active TβRII kinase to transphosphorylate and activate the TβRI kinase which, in turn, phosphorylates Smad2 and Smad3. Smad2/3 then associate with a common mediator Smad, Smad4, and translocate to the nucleus, where they regulate gene transcription. By contrast, the inhibitory Smad7 can interact with TβRI and prevent the phosphorylation of the effectors Smad2/3 (Massagué et al., 2000). In addition to Smads, more recently, other signaling pathways have been implicated in TGFβ actions. These include the extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol-3 kinase (PI3K), and Rho GTPases (reviewed in Derynck et al., 2001).
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