Fibroblast Growth Factor Receptor-Mediated Activation of AKT-β-Catenin-CBP Pathway Regulates Survival and Proliferation of Murine Hepatoblasts and Hepatic Tumor Initiating Stem Cells

Mavila, Nirmala; James, David; Utley, Sarah; Nguyen, Carvell T.; Coblens, Orly; Mak, Katrina; Rountree, C. Bart; Kahn, Michaël; Wang, Kasper S.

doi:10.1371/journal.pone.0050401

Cited by 42 publications

(56 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This paradigm appears to be generalizable to both epithelial and non-epithelial adult somatic stem/progenitor cells. In support of the universality of this model, similar ␤-catenin/co-activator interactions have been shown to regulate differentiation of other stem/progenitor cells including mouse and human embryonic stem cells (9,34), cardiovascular progenitors (35,36), neuronal progenitors (37), hepatoblasts and hepatic tumor initiating cells (38), and leukemia cells (39). This report extends these studies to elucidate a novel intersection between non-canonical and canonical signaling arms, further highlighting the complexity of Wnt signaling.…”

Section: Wnt5a/pkc/␤-catenin In Progenitor Cell Differentiationsupporting

confidence: 69%

p300/β-Catenin Interactions Regulate Adult Progenitor Cell Differentiation Downstream of WNT5a/Protein Kinase C (PKC)

Rieger

Zhou

Solomon

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Maintenance of stem/progenitor cell-progeny relationships is required for tissue homeostasis during normal turnover and repair. Wnt signaling is implicated in both maintenance and differentiation of adult stem/progenitor cells, yet how this pathway serves these dichotomous roles remains enigmatic. We previously proposed a model suggesting that specific interaction of ␤-catenin with either of the homologous Kat3 co-activators, p300 or CREB-binding protein, differentially regulates maintenance versus differentiation of embryonic stem cells. Limited knowledge of endogenous mechanisms driving differential ␤-catenin/co-activator interactions and their role in adult somatic stem/progenitor cell maintenance versus differentiation led us to explore this process in defined models of adult progenitor cell differentiation. We focused primarily on alveolar epithelial type II (AT2) cells, progenitors of distal lung epithelium, and identified a novel axis whereby WNT5a/protein kinase C (PKC) signaling regulates specific ␤-catenin/co-activator interactions to promote adult progenitor cell differentiation. p300/␤-catenin but not CBP/␤-catenin interaction increases as AT2 cells differentiate to a type I (AT1) cell-like phenotype. Additionally, p300 transcriptionally activates AT1 cell-specific gene Aqp-5. IQ-1, a specific inhibitor of p300/␤-catenin interaction, prevents differentiation of not only primary AT2 cells, but also tracheal epithelial cells, and C2C12 myoblasts. p300 phosphorylation at Ser-89 enhances p300/␤-catenin interaction, concurrent with alveolar epithelial cell differentiation. WNT5a, a traditionally non-canonical WNT ligand regulates Ser-89 phosphorylation and p300/␤-catenin interactions in a PKC-dependent manner, likely involving PKC. These studies identify a novel intersection of canonical and non-canonical Wnt signaling in adult progenitor cell differentiation that has important implications for targeting ␤-catenin to modulate adult progenitor cell behavior in disease.

show abstract

Section: Wnt5a/pkc/␤-catenin In Progenitor Cell Differentiationsupporting

confidence: 69%

p300/β-Catenin Interactions Regulate Adult Progenitor Cell Differentiation Downstream of WNT5a/Protein Kinase C (PKC)

Rieger

Zhou

Solomon

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Activated Akt, mediated by phosphorylation at T308 by PDK1 and phosphorylation at S473 by PDK2, regulates multiple downstream substrates including GSK3 α/β, FOXO, PRAS40 and TSC1/2 (32). Phosphorylation of S9 in GSK3β or S21 in GSK3α mediated by Akt can potentially lead to re-activation of β-catenin, which in turn can increase cyclin D1 and transcription factor activity leading to cell cycle progression (33–35). Increased phosphorylation of GSK3α at S21 and GSK3β at S9 was observed in both the resistant cell lines consistent with Akt activation.…”

Section: Discussionmentioning

confidence: 99%

Akt Activation Mediates Acquired Resistance to Fibroblast Growth Factor Receptor Inhibitor BGJ398

Datta

Damodaran

Parks

et al. 2017

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Activation of fibroblast growth factor receptor (FGFR) signaling through mutations, amplifications, or fusions involving FGFR1, 2, 3, or 4 are seen in multiple tumors including lung, bladder, and cholangiocarcinoma. Currently, several clinical trials are evaluating the role of novel FGFR inhibitors in solid tumors. As we move forward with FGFR inhibitors clinically, we anticipate emergence of resistance with treatment. Consequently, we sought to study the mechanism(s) of acquired resistance to FGFR inhibitors using annotated cancer cell lines. We identified cancer cell lines that have activating mutations in FGFR1, 2, or 3, and treated them chronically with the selective FGFR inhibitor, BGJ398. We observed resistance to chronic BGJ398 exposure in DMS114 (small cell lung cancer, FGFR1 amplification), and RT112 (urothelial carcinoma, FGFR3 fusion/amplification) cell lines based on viability assays. Reverse phase protein array (RPPA) analysis showed increased phosphorylation of Akt (T308 and S473) and its downstream target GSK3 (S9 and S21) in both the resistant cell lines when compared to matching controls. Results of RPPA were confirmed using immunoblots. Consequently, the addition of an Akt inhibitor (GSK2141795) or siRNA was able to restore sensitivity to BGJ398 in resistant cell lines. These data suggest a role for Akt pathway in mediating acquired resistance to FGFR inhibition.

show abstract

“…Complementary DNA synthesis was performed using iScript Reverse Transcription Supermix(Bio-Rad, Irvine, CA), and quantitative real-time PCR (qPCR) was performed as previously described [11, 13], using intron-spanning and gene-specific primers and probes designed using the Roche Universal Probe Library Assay Design Center (Roche, Basel, Switzerland) (see Supplemental Table 2 for primer sequences and probes).…”

Section: Methodsmentioning

confidence: 99%

Hepatic Prominin-1 expression is associated with biliary fibrosis

Nguyen

Zagory

Dietz

et al. 2017

Surgery

Self Cite

View full text Add to dashboard Cite

Background Intrahepatic biliary fibrosis, as seen with cholestatic liver injuries such as biliary atresia, is mechanistically distinct from fibrosis caused by hepatocyte toxicity. We previously demonstrated the expansion of cells expressing the stem/progenitor cell marker PROMININ-1 (PROM1), within regions of developing fibrosis in biliary atresia. Thus, we hypothesized that Prom1 expression is biliary fibrosis-specific. Methods Gene expression of Prom1 was analyzed in adult mice undergoing either cholestatic bile duct ligation (BDL) or hepatotoxic carbon tetrachloride (CCl4) administration by quantitative polymerase chair reaction. Lineage tracing of Prom1- expressing cells and Collagen-1α (Col1α)-expressing cells was performed after BDL in Prom1cre-ert2-lacz;Gfplsl and Col1αGfp transgenic mice, respectively. Results Prom1 expression increased significantly after BDL compared to sham (6.6±0.9 fold change at 2 weeks, p<0.05) but not with CCl4 (−0.7±0.5-fold change, NS). Upregulation of Prom1 was observed histologically throughout the liver as early as five days after BDL in Prom1cre-ert2-lacz mice by LacZ staining in non-hepatocyte cells. Lineage tracing of Prom1-expressing cells labeled prior to BDL in Prom1cre-ert2-lacz;Gfplsl mice, demonstrated increasing colocalization of GREEN FLUORESCENT PROTEIN (GFP) with biliary marker CYTOKERATIN-19 within ductular reactions up to 5 weeks after BDL consistent with biliary transdifferentiation. In contrast, rare colocalization of GFP with mesenchymal marker α-SMOOTH MUSCLE ACTIN in Prom1cre-ert2-lacz;Gfplsl mice and some colocalization of GFP with PROM1 in Col1αGfp mice, indicate minimal contribution of Prom1 progenitor cells to the pool of collagen-producing myofibroblasts. Conclusion During biliary fibrosis, Prom1-expressing progenitor cells transdifferentiate into cells within ductular reactions. This transdifferentiation may promote fibrosis.

show abstract

Fibroblast Growth Factor Receptor-Mediated Activation of AKT-β-Catenin-CBP Pathway Regulates Survival and Proliferation of Murine Hepatoblasts and Hepatic Tumor Initiating Stem Cells

Cited by 42 publications

References 47 publications

p300/β-Catenin Interactions Regulate Adult Progenitor Cell Differentiation Downstream of WNT5a/Protein Kinase C (PKC)

p300/β-Catenin Interactions Regulate Adult Progenitor Cell Differentiation Downstream of WNT5a/Protein Kinase C (PKC)

Akt Activation Mediates Acquired Resistance to Fibroblast Growth Factor Receptor Inhibitor BGJ398

Hepatic Prominin-1 expression is associated with biliary fibrosis

Contact Info

Product

Resources

About