Targeting the Transforming Growth FactorB Signaling Pathway in Human Cancer

TGF-β receptor signals through multiple signaling cascades. TGF-β activates Smad and non-Smad pathways. The ligand-activated TGFβRI and TGFβRII receptor complex recruits and phosphorylates the receptor specific R-Smads. The R-Smads are presented to the TGFβRI by a membrane-bound protein, SARA. R-Smad proteins are cytoplasmic molecules which, after receptor activation, associate with Co-Smad. Hetero-oligomeric complex of R-Smad-Co-Smad translocates to the nucleus and binds to specific DNA sequence and interacts with transcription factors (TF) and Co-factors (CF) to regulate transcription. R-Smads and Co-Smad shuttle between nucleus and cytoplasm. The pathway is negatively regulated by the I-Smads which binds activated TGFβRI, thereby preventing phosphorylation of R-Smads, or recruits the E3 ubiquitine ligases, Smurf1 and Smurf2 to induce proteosomal degradation of the R-Smads. STRAP interacts with TGFβRI and TGFβRII and with I-Smad, thus stabilizing the interaction of I-Smad with the receptor complex. Activation of the epidermal growth factor (EGF) receptor and other tyrosine kinase receptors, interferon (IFN)-γ signaling, and activation of NF-κB by tumor-necrosis factor (TNF)-α, also induce I-Smad expression, leading to inhibition of TGF-β signaling. Although the mechanism of activation of non-Smad pathways by the receptor complex remains largely unknown, these pathways are known to be involved in the pro-oncogenic responses to TGF-β in cooperation with or without Smad pathway. The activated receptor complex activates non-Smad signaling pathways, such as PI3K/Akt, Rho/Rac GTPases and Ras/MAPK and TAK1/MEKK1. TAK1 (TGF-β activated kinase 1) may mediate TGF-β effects with respect to the activation of distinct MAP kinase pathways (JNK, p38). TGF-β also induces activation of the Cdc42 GTPase which stimulates p21 activated kinase (PAK) downstream from Rac and Cdc42. TGF-β activation of PP2A, that inhibits S6K activity through the mTOR/FRAPPP2A-S6K pathway, mediates Smad-independent growth suppression. SBE: Smad binding element and TBE: Transcription factor binding element.

Publication

Targeting the Transforming Growth Factor-β Signaling Pathway in Human Cancer. () Nagathihalli S Nagaraj, et al. Expert Opin Investig Drugs. ;19(1):77-91. Figure: F1. All organisms Drosophila melanogaster Homo sapiens

Disease mentions