New insights into posttranslational modifications of Hippo pathway in carcinogenesis and therapeutics

He, Meiling; Zhou, Zhuan; Shah, Anil A.; Hong, Yang; Chen, Qianming; Wan, Yong

doi:10.1186/s13008-016-0013-6

Cited by 63 publications

(60 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Accumulating evidence suggests that the Hippo-YAP pathway is tightly regulated by various types of posttranslational modifications, including phosphorylation, ubiquitination, sumoylation, acetylation, etc. (66). Our study reveals a mechanistic link between neddylation and Hippo signaling.…”

Section: Discussionmentioning

confidence: 70%

Neddylation mediates ventricular chamber maturation through repression of Hippo signaling

Zou

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

During development, ventricular chamber maturation is a crucial step in the formation of a functionally competent postnatal heart. Defects in this process can lead to left ventricular noncompaction cardiomyopathy and heart failure. However, molecular mechanisms underlying ventricular chamber development remain incompletely understood. Neddylation is a posttranslational modification that attaches ubiquitin-like protein NEDD8 to protein targets via NEDD8-specific E1-E2-E3 enzymes. Here, we report that neddylation is temporally regulated in the heart and plays a key role in cardiac development. Cardiomyocyte-specific knockout of NAE1, a subunit of the E1 neddylation activating enzyme, significantly decreased neddylated proteins in the heart. Mice lacking NAE1 developed myocardial hypoplasia, ventricular noncompaction, and heart failure at late gestation, which led to perinatal lethality. NAE1 deletion resulted in dysregulation of cell cycle-regulatory genes and blockade of cardiomyocyte proliferation in vivo and in vitro, which was accompanied by the accumulation of the Hippo kinases Mst1 and LATS1/2 and the inactivation of the YAP pathway. Furthermore, reactivation of YAP signaling in NAE1-inactivated cardiomyocytes restored cell proliferation, and YAP-deficient hearts displayed a noncompaction phenotype, supporting an important role of Hippo-YAP signaling in NAE1-depleted hearts. Mechanistically, we found that neddylation regulates Mst1 and LATS2 degradation and that Cullin 7, a NEDD8 substrate, acts as the ubiquitin ligase of Mst1 to enable YAP signaling and cardiomyocyte proliferation. Together, these findings demonstrate a role for neddylation in heart development and, more specifically, in the maturation of ventricular chambers and also identify the NEDD8 substrate Cullin 7 as a regulator of Hippo-YAP signaling.

show abstract

Section: Discussionmentioning

confidence: 70%

Neddylation mediates ventricular chamber maturation through repression of Hippo signaling

Zou

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…LATS1 mRNA levels were not affected by MG in the three breast cancer cell lines (Figure 6—figure supplement 1A). A previous study has shown that LATS1 kinase degradation occurs through polyubiquitination and the proteasome pathway in breast cancer cells (He et al, 2016). In good accordance, the treatment of breast cancer cells with MG132 proteasome inhibitor induced LATS1 increase (Figure 6B).…”

Section: Resultsmentioning

confidence: 99%

Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP-mediated tumor growth and metastasis

Nokin

Durieux

Peixoto

et al. 2016

eLife

107

120

View full text Add to dashboard Cite

Metabolic reprogramming toward aerobic glycolysis unavoidably induces methylglyoxal (MG) formation in cancer cells. MG mediates the glycation of proteins to form advanced glycation end products (AGEs). We have recently demonstrated that MG-induced AGEs are a common feature of breast cancer. Little is known regarding the impact of MG-mediated carbonyl stress on tumor progression. Breast tumors with MG stress presented with high nuclear YAP, a key transcriptional co-activator regulating tumor growth and invasion. Elevated MG levels resulted in sustained YAP nuclear localization/activity that could be reverted using Carnosine, a scavenger for MG. MG treatment affected Hsp90 chaperone activity and decreased its binding to LATS1, a key kinase of the Hippo pathway. Cancer cells with high MG stress showed enhanced growth and metastatic potential in vivo. These findings reinforce the cumulative evidence pointing to hyperglycemia as a risk factor for cancer incidence and bring renewed interest in MG scavengers for cancer treatment.DOI: http://dx.doi.org/10.7554/eLife.19375.001

show abstract

“…Decreased YAP phosphorylation can favor YAP retention in the nucleus. Phosphorylation of YAP at Ser-397 promotes its proteolytic degradation (18). The ratio of Ser-397 phosphorylated YAP to total YAP also decreased 7 days after TAC ( Fig.…”

Section: Yap Is Activated In Response To Pomentioning

confidence: 82%

Yes-associated protein (YAP) mediates adaptive cardiac hypertrophy in response to pressure overload

Byun

Zhai

et al. 2019

Journal of Biological Chemistry

View full text Add to dashboard Cite

New insights into posttranslational modifications of Hippo pathway in carcinogenesis and therapeutics

Cited by 63 publications

References 53 publications

Neddylation mediates ventricular chamber maturation through repression of Hippo signaling

Neddylation mediates ventricular chamber maturation through repression of Hippo signaling

Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP-mediated tumor growth and metastasis

Yes-associated protein (YAP) mediates adaptive cardiac hypertrophy in response to pressure overload

Contact Info

Product

Resources

About