Figure 1. TMEPAI modulates TGF-β signaling.

Exposure of cells to active TGF-β leads to assembly of the tetrameric receptor complex, composed of two type I and two type II TGF-β receptor subunits (TGFBRI and TGFBRII). TGFBRII then phosphorylates TGFBRI, enabling it to activate downstream signaling pathways. In the canonical signaling pathway (left), TGFBRI phosphorylates receptor SMADs (SMAD2/3), which can then associate with SMAD4 and become translocated to the nucleus. The SMAD signaling complex can inhibit cell proliferation by inhibiting expression of MYC and increasing expression of p21CIP1 and p15INK4b. In the noncanonical signaling pathway (right), the activated TGF-β receptor complex regulates SMAD-independent pathways, including activation of Rho family members, and can stimulate cellular proliferation through activation of MAPK and PI3K/Akt. In triple negative breast cancer cell lines, expression of TMEPAI blocks canonical signaling through sequestration of SMAD4 and potentiates the noncanonical activation of PI3K/Akt by downregulating the PI3K inhibitor PTEN.