Critical Roles of Phosphoinositides and NF2 in Hippo Pathway Regulation

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2020 Mar 3

PMID 32115406

Citations 32

Authors

Audrey W Hong

Zhipeng Meng

Steven W Plouffe

Zhijie Lin

Mingjie Zhang

Kun-Liang Guan

Affiliations

Soon will be listed here.

Abstract

The Hippo pathway is a master regulator of tissue homeostasis and organ size. NF2 is a well-established tumor suppressor, and loss of NF2 severely compromises Hippo pathway activity. However, the precise mechanism of how NF2 mediates upstream signals to regulate the Hippo pathway is not clear. Here we report that, in mammalian cells, NF2's lipid-binding ability is critical for its function in activating the Hippo pathway in response to osmotic stress. Mechanistically, osmotic stress induces PI(4,5)P plasma membrane enrichment by activating the PIP5K family, allowing for NF2 plasma membrane recruitment and subsequent downstream Hippo pathway activation. An NF2 mutant deficient in lipid binding is unable to activate the Hippo pathway in response to osmotic stress, as measured by LATS and YAP phosphorylation. Our findings identify the PIP5K family as novel regulators upstream of Hippo signaling, and uncover the importance of phosphoinositide dynamics, specifically PI(4,5)P, in Hippo pathway regulation.

Citing Articles

Phosphoinositide signaling in the nucleus: Impacts on chromatin and transcription regulation.

Hifdi N, Vaucourt M, Hnia K, Panasyuk G, Vandromme M Biol Cell. 2024; 117(1):e2400096.

PMID: 39707648 PMC: 11771838. DOI: 10.1111/boc.202400096.

Functional annotation of the Hippo pathway somatic mutations in human cancers.

Han H, Huang Z, Xu C, Seo G, An J, Yang B Nat Commun. 2024; 15(1):10106.

PMID: 39572544 PMC: 11582751. DOI: 10.1038/s41467-024-54480-y.

Retinoic acid-induced protein 14 links mechanical forces to Hippo signaling.

Jeong W, Kwon H, Park S, Lee I, Jho E EMBO Rep. 2024; 25(9):4033-4061.

PMID: 39160347 PMC: 11387738. DOI: 10.1038/s44319-024-00228-0.

Hippo and PI5P4K signaling intersect to control the transcriptional activation of YAP.

Palamiuc L, Johnson J, Haratipour Z, Loughran R, Choi W, Arora G Sci Signal. 2024; 17(838):eado6266.

PMID: 38805583 PMC: 11283293. DOI: 10.1126/scisignal.ado6266.

The immunometabolic function of VGLL3 and female-biased autoimmunity.

Kennicott K, Liang Y Immunometabolism (Cobham). 2024; 6(2):e00041.

PMID: 38726338 PMC: 11078290. DOI: 10.1097/IN9.0000000000000041.

References

Pedersen S, Kapus A, Hoffmann E . Osmosensory mechanisms in cellular and systemic volume regulation. J Am Soc Nephrol. 2011; 22(9):1587-97. DOI: 10.1681/ASN.2010121284. View

Lundmark R, Doherty G, Vallis Y, Peter B, McMahon H . Arf family GTP loading is activated by, and generates, positive membrane curvature. Biochem J. 2008; 414(2):189-94. PMC: 2518064. DOI: 10.1042/BJ20081237. View

Li Y, Zhou H, Li F, Chan S, Lin Z, Wei Z . Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway. Cell Res. 2015; 25(7):801-17. PMC: 4493278. DOI: 10.1038/cr.2015.69. View

McClatchey A, Saotome I, Mercer K, Crowley D, Gusella J, Bronson R . Mice heterozygous for a mutation at the Nf2 tumor suppressor locus develop a range of highly metastatic tumors. Genes Dev. 1998; 12(8):1121-33. PMC: 316711. DOI: 10.1101/gad.12.8.1121. View

BOSHANS R, Szanto S, Van Aelst L, DSouza-Schorey C . ADP-ribosylation factor 6 regulates actin cytoskeleton remodeling in coordination with Rac1 and RhoA. Mol Cell Biol. 2000; 20(10):3685-94. PMC: 85663. DOI: 10.1128/MCB.20.10.3685-3694.2000. View

Liu A, Sui D, Wu D, Hu J . The activation loop of PIP5K functions as a membrane sensor essential for lipid substrate processing. Sci Adv. 2017; 2(11):e1600925. PMC: 5262455. DOI: 10.1126/sciadv.1600925. View

Xiao G, Chernoff J, Testa J . NF2: the wizardry of merlin. Genes Chromosomes Cancer. 2003; 38(4):389-99. DOI: 10.1002/gcc.10282. View

Jones D, Morris J, Morgan C, Kondo H, Irvine R, Cockcroft S . Type I phosphatidylinositol 4-phosphate 5-kinase directly interacts with ADP-ribosylation factor 1 and is responsible for phosphatidylinositol 4,5-bisphosphate synthesis in the golgi compartment. J Biol Chem. 2000; 275(18):13962-6. DOI: 10.1074/jbc.c901019199. View

Honda A, Nogami M, Yokozeki T, Yamazaki M, Nakamura H, Watanabe H . Phosphatidylinositol 4-phosphate 5-kinase alpha is a downstream effector of the small G protein ARF6 in membrane ruffle formation. Cell. 1999; 99(5):521-32. DOI: 10.1016/s0092-8674(00)81540-8. View

10.

Hamaratoglu F, Willecke M, Kango-Singh M, Nolo R, Hyun E, Tao C . The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat Cell Biol. 2005; 8(1):27-36. DOI: 10.1038/ncb1339. View

11.

Shaw R, Paez J, Curto M, Yaktine A, Pruitt W, Saotome I . The Nf2 tumor suppressor, merlin, functions in Rac-dependent signaling. Dev Cell. 2001; 1(1):63-72. DOI: 10.1016/s1534-5807(01)00009-0. View

12.

Plouffe S, Hong A, Guan K . Disease implications of the Hippo/YAP pathway. Trends Mol Med. 2015; 21(4):212-22. PMC: 4385444. DOI: 10.1016/j.molmed.2015.01.003. View

13.

Pan D . The hippo signaling pathway in development and cancer. Dev Cell. 2010; 19(4):491-505. PMC: 3124840. DOI: 10.1016/j.devcel.2010.09.011. View

14.

Ishihara H, Shibasaki Y, Kizuki N, Katagiri H, Yazaki Y, Asano T . Cloning of cDNAs encoding two isoforms of 68-kDa type I phosphatidylinositol-4-phosphate 5-kinase. J Biol Chem. 1996; 271(39):23611-4. DOI: 10.1074/jbc.271.39.23611. View

15.

Hornbeck P, Kornhauser J, Latham V, Murray B, Nandhikonda V, Nord A . 15 years of PhosphoSitePlus®: integrating post-translationally modified sites, disease variants and isoforms. Nucleic Acids Res. 2018; 47(D1):D433-D441. PMC: 6324072. DOI: 10.1093/nar/gky1159. View

16.

Yin F, Yu J, Zheng Y, Chen Q, Zhang N, Pan D . Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2. Cell. 2013; 154(6):1342-55. PMC: 3835333. DOI: 10.1016/j.cell.2013.08.025. View

17.

Surace E, Haipek C, Gutmann D . Effect of merlin phosphorylation on neurofibromatosis 2 (NF2) gene function. Oncogene. 2004; 23(2):580-7. DOI: 10.1038/sj.onc.1207142. View

18.

Loijens J, Anderson R . Type I phosphatidylinositol-4-phosphate 5-kinases are distinct members of this novel lipid kinase family. J Biol Chem. 1996; 271(51):32937-43. DOI: 10.1074/jbc.271.51.32937. View

19.

Halder G, Johnson R . Hippo signaling: growth control and beyond. Development. 2010; 138(1):9-22. PMC: 2998162. DOI: 10.1242/dev.045500. View

20.

Fievet B, Gautreau A, Roy C, Del Maestro L, Mangeat P, Louvard D . Phosphoinositide binding and phosphorylation act sequentially in the activation mechanism of ezrin. J Cell Biol. 2004; 164(5):653-9. PMC: 2172172. DOI: 10.1083/jcb.200307032. View