Mammalian Ste20-Like Kinase and SAV1 Promote 3T3-L1 Adipocyte Differentiation by Activation of PPARγ

Abstract

The mammalian ste20 kinase (MST) signaling pathway plays an important role in the regulation of apoptosis and cell cycle control. We sought to understand the role of MST2 kinase and Salvador homolog 1 (SAV1), a scaffolding protein that functions in the MST pathway, in adipocyte differentiation. MST2 and MST1 stimulated the binding of SAV1 to peroxisome proliferator-activated receptor γ (PPARγ), a transcription factor that plays a key role in adipogenesis. The interaction of endogenous SAV1 and PPARγ was detected in differentiating 3T3-L1 adipocytes. This binding required the kinase activity of MST2 and was mediated by the WW domains of SAV1 and the PPYY motif of PPARγ. Overexpression of MST2 and SAV1 increased PPARγ levels by stabilizing the protein, and the knockdown of SAV1 resulted in a decrease of endogenous PPARγ protein in 3T3-L1 adipocytes. During the differentiation of 3T3-L1 cells into adipocytes, MST2 and SAV1 expression began to increase at 2 days when PPARγ expression also begins to increase. MST2 and SAV1 significantly increased PPARγ transactivation, and SAV1 was shown to be required for the activation of PPARγ by rosiglitazone. Finally, differentiation of 3T3-L1 cells was augmented by MST2 and SAV1 expression and inhibited by knockdown of MST1/2 or SAV1. These results suggest that PPARγ activation by the MST signaling pathway may be a novel regulatory mechanism of adipogenesis.

SOX2 Regulates YAP1 to Maintain Stemness and Determine Cell Fate in the Osteo-Adipo Lineage

“…Indeed, although SOX2 mRNA and protein are both induced during adipogenesis, YAP1 mRNA levels increase during adipogenesis, in line with its being a SOX2 target, but the protein is decreased. Thus, it is likely that additional posttranscriptional mechanisms, such as activation of the proadipogenic effect of components of the Hippo pathway (Park et al, 2012a), may restrain YAP1 protein levels during adipogenesis, which appears to be exquisitely sensitive to the concentration of YAP1. Elevated YAP1 strongly induces proliferation in MSCs (U.B.R.…”

“…Elevated YAP1 strongly induces proliferation in MSCs (U.B.R. and A.M., unpublished data) that could counteract the proadipogenic effect of MST and Sav1 components of the Hippo pathway (Park et al, 2012a). In line with this, we find that YAP1 overexpression inhibits expression of PPARγ, which is reduced upon YAP1 depletion.…”

Hippo vs. Crab: tissue‐specific functions of the mammalian Hippo pathway

“…Although inhibition of MST1/2 or SAV1 blocks adipogenesis in vitro (Park et al . ), it is not known whether this effect depends on canonical Hippo‐YAP1/TAZ signaling or on an alternative pathway (Park et al . ).…”

“…Normal vs tumorigenic Hippo signaling C (SP-C) (Park et al 2004). However, a lack of Mst1/2 in murine lung epithelial cells results in perinatal lethality associated with an increase in immature pneumocytes that cannot express SP-C, similar to human respiratory distress syndrome (RDS) Lange et al 2015;Lin et al 2015).…”

The non-canonical Hippo/Mst pathway in lymphocyte development and functions

“…MST1 can impair insulin secretion by phosphorylating and destabilizing the β-cell transcription factor PDX1 [12]. Mst2-Sav1 complex promotes adipocyte differentiation by stabilizing and activating PPARγ [13]. Mst1-Ndr1 signaling promotes stable kinetochore-microtubule attachment by restraining Aurora B activity and centrosome duplication, whereas the Mst1-Sav1 complex regulates centrosome disjunction via Nek2A [14][15][16].…”