Cross‐talk between the TGFβ and Wnt signaling pathways in murine embryonic maxillary mesenchymal cells

Abstract

The transforming growth factor beta (TGFb) and Wnt signaling pathways play central roles regulating embryogenesis and maintaining adult tissue homeostasis. TGFb mediates its cellular effects through types I and II cell surface receptors coupled to the nucleocytoplasmic Smad proteins. Wnt signals via binding to a cell surface receptor, Frizzled, which in turn activates intracellular Dishevelled, ultimately leading to stabilization and nuclear translocation of b-catenin. Previous studies have demonstrated several points of cross-talk between the TGFb and Wnt signaling pathways. In yeast two-hybrid and GST-pull down assays, Dishevelled-1 and Smad 3 have been shown to physically interact through the C-terminal one-half of Dishevelled-1 and the MH2 domain of Smad 3. The current study demonstrates that co-treatment of murine embryonic maxillary mesenchyme (MEMM) cells with Wnt-3a and TGFb leads to enhanced reporter activity from TOPflash, a Wnt-responsive reporter plasmid. Transcriptional cooperation between TGFb and Wnt did not require the presence of a Smad binding element, nor did it occur when a TGFb-responsive reporter plasmid (p3TP-lux) was transfected. Overexpression of Smad 3 further enhanced the cooperation between Wnt and TGFb while overexpression of dominant-negative Smads 2 and 3 inhibited this effect. Co-stimulation with TGFb led to greater nuclear translocation of b-catenin, providing explanation for the effect of TGFb on Wnt-3a reporter activity. Wnt-3a exerted antiproliferative activity in MEMM cells, similar to that exerted by TGFb. In addition, Wnt-3a and TGFb in combination led to synergistic decreases in MEMM cell proliferation. These data demonstrate a functional interaction between the TGFb and Wnt signaling pathways and suggest that Wnt activation of the canonical pathway is an important mediator of MEMM cell growth.

Yamanaka factors critically regulate the developmental signaling network in mouse embryonic stem cells

“…MAPK/ERK signaling is active in undifferentiated human ES cells and is down-regulated upon differentiation [48]. These signaling pathways may thus constitute a complex signaling network actively maintaining ES cell pluripotency [49][50][51][52][53][54][55][56][57][58][59].…”

Transforming Growth Factor-β Stimulates Cyclin D1 Expression through Activation of β-Catenin Signaling in Chondrocytes

“…In mesenchymal stem cells, ␤-catenin inhibits chondrogenesis and causes cells to differentiate toward an osteoblast phenotype (32). Interestingly, TGF-␤ and SMAD3 have been shown to enhance ␤-catenin signaling in embryonic maxillary mesenchymal cells (36). In prehypertrophic and hypertrophic chondrocytes committed to maturation, ␤-catenin induces terminal differentiation (6,34).…”

SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice

“…This reporter construct has been shown to be efficiently stimulated by Wnt1 in a variety of cell lines. [36][37][38][39][40][41][42] TOPflash or FOPflash reporter plasmid was transiently transfected in the HEK-293 cell line, in which both Wnt and its Wnt/␤-catenin signal pathways were present. TOPflash reporter plasmid was also cotransfected with SALL4A or SALL4B.…”