Non-Smad pathways in TGF-beta signaling

Abstract

Transforming growth factor-beta utilizes a multitude of intracellular signaling pathways in addition to Smads to regulate a wide array of cellular functions. These non-canonical, non-Smad pathways are activated directly by ligand-occupied receptors to reinforce, attenuate, or otherwise modulate downstream cellular responses. These non-Smad pathways include various branches of MAP kinase pathways, Rho-like GTPase signaling pathways, and phosphatidylinositol-3-kinase/AKT pathways. This review focuses on recent advances in the understanding of the molecular and biochemical mechanisms of non-Smad pathways. In addition, functions of these non-Smad pathways are also discussed.

Figure 1

The Erk non-Smad pathway. TGF-β can induce phosphorylation of tyrosine residues on both type I and type II receptors and/or on Shc. The phosphorylated tyrosines are capable of recruiting Grb2/Sos to activate Erk through Ras, Raf, and their downstream MAPK cascades. Erk then regulates target gene transcription through its downstream transcription factors in conjunction with Smads to control EMT. Erk can also inhibit R-Smad activities through phosphorylation of R-Smads.

Figure 2

The JNK/p38 non-Smad pathway. TGF-β receptors interact with TRAF6 and induce the formation of K63-linked poly-ubiquitin chains on TRAF6. Poly-ubiquitinated TRAF6 recruits TAK1 to activate JNK/p38. Activated JNK/p38 act in conjunction with Smads to regulate apoptosis and EMT by controlling the activities of downstream transcription factors. JNK can also regulate R-Smad activity directly by phosphorylation.

Figure 3

The Small GTPase non-Smad pathway. RhoA can be activated by TGF-β via either Smad-dependent or independent routes to induce actin stress fiber formation during EMT. TGF-β also induces the dissolution of tight junctions during EMT by recruiting Cdc42 to the receptor complex, and by triggering degradation of RhoA at cellular protrusions. TGF-β-induced RhoA degradation requires phosphorylation of Par6 by TβRII and the Smurf1 E3 ligase.

Figure 4

The PI3K/Akt non-Smad pathway. TGF-β can activate PI3K and Akt, possibly by inducing a physical interaction between the p85 subunit of PI3K and the receptors. The activated PI3K/Akt pathway then controls translational responses through mTOR/S6K, which collaborates with Smad-mediated transcriptional responses during EMT. In the growth arrest response, TGF-β may inhibit S6K by inducing an interaction between the Bα subunit of PP2A and the receptors. Akt is also capable of antagonizing TGF-β-induced apoptosis and growth arrest by sequestering Smad3 in the cytoplasm and by inhibiting the activity of FoxO transcription factor.