Phosphorylation of the Hippo Pathway Component AMOTL2 by the mTORC2 Kinase Promotes YAP Signaling, Resulting in Enhanced Glioblastoma Growth and Invasiveness

Artinian, Nicholas; Cloninger, Cheri; Holmes, Brent; Benavides-Serrato, Angelica; Bashir, Tariq; Gera, Joseph

doi:10.1074/jbc.m115.656587

Cited by 87 publications

(92 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…During branching morphogenesis, the proximal-peripheral axis of the lung is demarcated by the mutually exclusive expression of SOX2 (in conducting) and SOX9 in acinar (peripheral) buds of the embryonic lung (22,26). Consistent with present single-cell RNA studies, we found a paucity of SOX2 and other conducting airway markers in the normal alveolar epithelium (Figure 4) (26,28,(33)(34)(35)(36). In sharp contrast, SOX2 RNA was coexpressed with many AT2 cell-related gene markers (e.g., SFTPA2, CTSH, LPCAT, SCD), including goblet and basal cell-associated RNAs (e.g., P63, KRT5, 6AB, ITGB4, PAX9, MUC5AC, and MUC5B) in IPF.…”

Section: Discussionsupporting

confidence: 76%

Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis

et al. 2016

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 76%

Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis

et al. 2016

View full text Add to dashboard Cite

“…Cells and organisms must adjust to fluctuating nutrient levels, especially during development and regeneration [2,47,48]. Crosstalk between potent cellular growth pathways, such as the Hippo and mTOR pathways, on multiple levels is crucial to maintain homeostasis [1,45,[49][50][51][52]. This report shows that cells with high YAP/TAZ activity gain an enhanced ability of acquiring nutrients to support biosynthesis and growth.…”

Section: Discussionmentioning

confidence: 89%

The Hippo pathway effectors YAP and TAZ promote cell growth by modulating amino acid signaling to mTORC1

et al. 2015

View full text Add to dashboard Cite

YAP and TAZ are transcriptional co-activators and function as the major effectors of the Hippo tumor suppressor pathway, which controls cell growth, tissue homeostasis, and organ size. Here we show that YAP/TAZ play an essential role in amino acid-induced mTORC1 activation, particularly under nutrient-limiting conditions. Mechanistically, YAP/TAZ act via the TEAD transcription factors to induce expression of the high-affinity leucine transporter LAT1, which is a heterodimeric complex of SLC7A5 and SLC3A2. Deletion of YAP/TAZ abolishes expression of LAT1 and reduces leucine uptake. Re-expression of SLC7A5 in YAP/TAZ knockout cells restores leucine uptake and mTORC1 activation. Moreover, SLC7A5 knockout cells phenocopies YAP/TAZ knockout cells which exhibit defective mTORC1 activation in response to amino acids. We further demonstrate that YAP/TAZ act through SLC7A5 to provide cells with a competitive growth advantage. Our study provides molecular insight into the mechanism of YAP/TAZ target genes in cell growth regulation.

show abstract

“…Since our previous work and that of others have demonstrated that GBMs have an elevated expression of YAP (Artinian et al, 2015; Orr et al, 2011; Xu et al, 2010), we also investigated whether a brachyury-driven mechanism of YAP regulation might be co-opted in the primary cultures of GBM cells. A significant decrease in YAP protein and mRNA expression were observed in primary GBM cells silenced for brachyury expression (Fig.…”

Section: Resultsmentioning

confidence: 99%

Brachyury-YAP Regulatory Axis Drives Stemness and Growth in Cancer

et al. 2017

View full text Add to dashboard Cite

SUMMARY Molecular factors that define stem cell identity have recently emerged as oncogenic drivers. For instance, brachyury, a key developmental transcriptional factor, is also implicated in carcinogenesis, most notably of chordoma, through mechanisms that remain elusive. Here, we show that brachyury is a crucial regulator of stemness in chordoma and in more common aggressive cancers. Furthermore, this effect of brachyury is mediated by control of synthesis and stability of Yes-associated protein (YAP), a key regulator of tissue growth and homeostasis, providing an unexpected mechanism of control of YAP expression. We further demonstrate that the Brachyury-YAP regulatory pathway is associated with tumor aggressiveness. These results elucidate a mechanism of controlling both tumor stemness and aggressiveness through regulatory coupling of two developmental factors.

show abstract

Phosphorylation of the Hippo Pathway Component AMOTL2 by the mTORC2 Kinase Promotes YAP Signaling, Resulting in Enhanced Glioblastoma Growth and Invasiveness

Cited by 87 publications

References 45 publications

Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis

Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis

The Hippo pathway effectors YAP and TAZ promote cell growth by modulating amino acid signaling to mTORC1

Brachyury-YAP Regulatory Axis Drives Stemness and Growth in Cancer

Contact Info

Product

Resources

About