TGFβ‐induced TAZ upregulation and the underlying mechanisms

Abstract

TGFβ is a prime inducer of myofibroblast (MF) transition from various precursors. TAZ, a Hippo pathway‐regulated transcriptional coactivator has been shown to crosstalk with TGFβ signaling, primarily as a Smad3 nuclear retention factor. During our studies aimed at assessing the role of TAZ in fibrogenic phenotype shifts, we observed that TGFβ caused a substantial (»5‐fold) and fast (6 h) rise in TAZ protein level in two MF precursors, pericyte‐like (10T1/2) cells and renal fibroblasts. TGFβ increased TAZ in tubular epithelial cells as well, an effect that was strongly potentiated by cell contact uncoupling, a prerequisite for epithelial‐MF transition. Interrogating the underlying signaling in 10T1/2 cells, we found that the Smad3 inhibitor SIS3 failed to abolish TGFβ‐induced TAZ upregulation, whereas inhibition of Akt or p38 abrogated this effect. These findings imply that non‐canonical TGFβ pathways are central to the control of TAZ. While interference with TAZ‐degrading pathways (Casein Kinase δ/ε, GSK3β) increased TAZ expression with similar magnitude and kinetics as TGFβ, cycloheximide‐provoked TAZ degradation was not prevented by TGFβ. Instead, TGFβ increased TAZ mRNA. Since myocardin‐related transcription factor (MRTF) is a TGFβ‐regulated key inducer of MF transition, we treated cells with its inhibitor, CCG‐1423. The drug strongly suppressed TGFβ‐triggered TAZ expression and the concomitant induction of a TAZ‐dependent luciferase reporter. Thus, TGFβ enhances TAZ transcription in an Akt‐, p38‐ and MRTF‐dependent manner, signifying a hitherto under‐recognized TAZ regulatory mechanism with potentially key roles in the pathobiology of organ fibrosis.