Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth

被引：78

作者：

Cox, Andrew G. ^{[1
,13
,14
,15
]}

Tsomides, Allison ^{[1
]}

Yimlamai, Dean ^{[2
,16
]}

Hwang, Katie L. ^{[1
,3
]}

Miesfeld, Joel ^{[4
]}

Galli, Giorgio G. ^{[2
,17
]}

Fowl, Brendan H. ^{[2
]}

Fort, Michael ^{[1
]}

Ma, Kimberly Y. ^{[1
]}

Sullivan, Mark R. ^{[5
]}

Hosios, Aaron M. ^{[5
]}

Snay, Erin ^{[2
]}

Yuan, Min ^{[6
]}

Brown, Kristin K. ^{[6
]}

Lien, Evan C. ^{[5
,6
]}

Chhangawala, Sagar ^{[7
,8
]}

Steinhauser, Matthew L. ^{[1
,9
,10
]}

Asara, John M. ^{[6
]}

Houvras, Yariv ^{[7
,8
]}

Link, Brian ^{[4
]}

Vander Heiden, Matthew G. ^{[5
,11
]}

Camargo, Fernando D. ^{[2
,9
]}

Goessling, Wolfram ^{[1
,9
,10
,11
,12
]}

机构：

[1] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02115 USA

[2] Harvard Med Sch, Boston Childrens Hosp, Boston, MA USA

[3] Harvard Med Sch, Harvard MIT MD PhD Program, Boston, MA USA

[4] Med Coll Wisconsin, Milwaukee, WI 53226 USA

[5] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[6] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA USA

[7] Weill Cornell Med Coll, New York, NY USA

[8] New York Presbyterian Hosp, New York, NY USA

[9] Harvard Stem Cell Inst, Cambridge, MA 02138 USA

[10] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[11] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA

[12] Harvard MIT Div Hlth Sci & Technol, Boston, MA 02139 USA

[13] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[14] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic, Australia

[15] Univ Melbourne, Dept Biochem & Mol Biol, Parkville, Vic, Australia

[16] Univ Pittsburgh, Childrens Hosp Pittsburgh, Med Ctr, Pittsburgh, PA 15213 USA

[17] Novartis Inst BioMed Res, Dis Area Oncol, Basel, Switzerland

来源：

EMBO JOURNAL | 2018年 / 37卷 / 22期

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

Hippo pathway; Yap; glut1; glucose metabolism; liver development; AMPK-MEDIATED REGULATION; HIPPO PATHWAY ACTIVITY; TEMPORAL REQUIREMENT; TISSUE HOMEOSTASIS; GENE-EXPRESSION; SIZE-CONTROL; CELL-GROWTH; IN-VIVO; CANCER; LIVER;

D O I：

10.15252/embj.2018100294

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The Hippo pathway and its nuclear effector Yap regulate organ size and cancer formation. While many modulators of Hippo activity have been identified, little is known about the Yap target genes that mediate these growth effects. Here, we show that yap(-/-) mutant zebrafish exhibit defects in hepatic progenitor potential and liver growth due to impaired glucose transport and nucleotide biosynthesis. Transcriptomic and metabolomic analyses reveal that Yap regulates expression of glucose transporter glut1, causing decreased glucose uptake and use for nucleotide biosynthesis in yap(-/-) mutants, and impaired glucose tolerance in adults. Nucleotide supplementation improves Yap deficiency phenotypes, indicating functional importance of glucose-fueled nucleotide biosynthesis. Yap-regulated glut1 expression and glucose uptake are conserved in mammals, suggesting that stimulation of anabolic glucose metabolism is an evolutionarily conserved mechanism by which the Hippo pathway controls organ growth. Together, our results reveal a central role for Hippo signaling in glucose metabolic homeostasis.

引用

页数：16

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