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. 2020 Oct 13;21(20):7532. doi: 10.3390/ijms21207532

Figure 3.

Figure 3

(A) Opposing modulatory effects of TRIM25 and TRIM47 on TGFβ-Smad signaling in the GI tract. TRIM25 induces the TGFβ signaling pathway as indicated from the increased phospho- Smad2 and Smad4 levels. Thereby, the activated Co-Smad/R-Smad complex transclocates into the nucleus and modulates transcription of target genes either in a positive (green symbol) or in a negative manner (red symbol). Whether in CRC TRIM25 may additionally promote the activation of R-Smad proteins by the TβRI through activation of Itch E3 ligase AIP4 through non-degradative ubiquitin modification remains questionable (question mark). In clear contrast, TRIM47 negatively interferes with TGFβ-Smad-signaling mainly by increasing ubiquitination and degradation of the Co-Smad protein Smad4. TRIMs with a stimulatory effect on the TGFβ-Smad signaling pathway are marked in green; TRIMs with an inhibitory effect are depicted in red. AIP4: Atrophin 1-interacting protein; CTGF: connective tissue growth factor; PAI: plasminogen activator inhibitor; R-Smads: receptor-Smads; TβR: TGFβ-receptor. (B) TRIM activation of PI3K/Akt signaling in CRC is executed by diverse mechanisms. TRIM59 promotes migration and invasion of CRC cells through direct activation of the PI3K/Akt pathway by an unknown mechanism, presumably through increasing tyrosine phosphorylation (pY) of the PI3k. TRIM14 enhances the PI3K-dependent phosphorylation of PIP2 to PIP3 indirectly through promoting the ubiqutination and subsequent proteasomal degradation of PTEN, an intrinsic antagonist of the PI3K. TRIM27 promotes proliferation and EMT of CRC cells mainly through increasing Akt phosphorylation. As a further consequence, phosphorylated Akt reduces β-catenin phosphorylation by GSK-3β resulting in an activation of EMT. Whether TRIM27 additionally facilitates ubiquitin-triggered degradation of PTEN is still questionable. TRIM44 activates the Akt/mTOR signaling pathway and its downstream target mTOR which, inter alia, results in the activation of the mitogenic p70 S6 kinase. TRIMs with a stimulatory effect on the PI3K/Akt signaling pathway are depicted in green. mTOR: mechanistic target of rapamycin; PIP2: phosphatidylinositol 4,5 bisphosphate (PIP2); PIP3: phosphatidylinositol 3,4,5 triphosphate; PDK1: phosphoinositide dependent protein kinase 1; PTEN: phosphatase and tensin homologue protein; RTK: receptor tyrosine kinase; p70S6K: p70 S6 kinase.