Hypoxia-inducible Factor 1 Regulation Through Cross Talk Between MTOR and MT1-MMP

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2013 Oct 30

PMID 24164895

Citations 38

Authors

Takeharu Sakamoto

Jane S Weng

Toshiro Hara

Seiko Yoshino

Hiroko Kozuka-Hata

Masaaki Oyama

Motoharu Seiki

Affiliations

Soon will be listed here.

Abstract

Hypoxia-inducible factor 1 (HIF-1) plays a key role in the cellular adaptation to hypoxia. Although HIF-1 is usually strongly suppressed by posttranslational mechanisms during normoxia, HIF-1 is active and enhances tumorigenicity in malignant tumor cells that express the membrane protease MT1-MMP. The cytoplasmic tail of MT1-MMP, which can bind a HIF-1 suppressor protein called factor inhibiting HIF-1 (FIH-1), promotes inhibition of FIH-1 by Mint3 during normoxia. To explore possible links between HIF-1 activation by MT1-MMP/Mint3 and tumor growth signals, we surveyed a panel of 252 signaling inhibitors. The mTOR inhibitor rapamycin was identified as a possible modulator, and it inhibited the mTOR-dependent phosphorylation of Mint3 that is required for FIH-1 inhibition. A mutant Mint3 protein that cannot be phosphorylated exhibited a reduced ability to inhibit FIH-1 and promoted tumor formation in mice. These data suggest a novel molecular link between the important hub proteins MT1-MMP and mTOR that contributes to tumor malignancy.

Citing Articles

Mint3 as a Molecular Target Activated in the Early Stage of Hepatocarcinogenesis.

Nishitani M, Okada H, Nio K, Hayashi T, Terashima T, Iida N Int J Mol Sci. 2025; 26(4).

PMID: 40003897 PMC: 11855386. DOI: 10.3390/ijms26041430.

Inflammation in atherosclerosis: pathophysiology and mechanisms.

Ajoolabady A, Pratico D, Lin L, Mantzoros C, Bahijri S, Tuomilehto J Cell Death Dis. 2024; 15(11):817.

PMID: 39528464 PMC: 11555284. DOI: 10.1038/s41419-024-07166-8.

Macrophage energy metabolism in cardiometabolic disease.

Wong A, Sun Q, Latif I, Karwi Q Mol Cell Biochem. 2024; 480(3):1763-1783.

PMID: 39198360 PMC: 11842501. DOI: 10.1007/s11010-024-05099-6.

Mmp14-dependent remodeling of the pericellular-dermal collagen interface governs fibroblast survival.

Sabeh F, Li X, Olson A, Botvinick E, Kurup A, Gimenez L J Cell Biol. 2024; 223(9.

PMID: 38990714 PMC: 11244150. DOI: 10.1083/jcb.202312091.

mTOR signaling is required for phagocyte free radical production, GLUT1 expression, and control of infection.

Genito C, Darwitz B, Reber C, Moorman N, Graves C, Monteith A mBio. 2024; 15(6):e0086224.

PMID: 38767353 PMC: 11324022. DOI: 10.1128/mbio.00862-24.

References

Hara T, Mimura K, Abe T, Shioi G, Seiki M, Sakamoto T . Deletion of the Mint3/Apba3 gene in mice abrogates macrophage functions and increases resistance to lipopolysaccharide-induced septic shock. J Biol Chem. 2011; 286(37):32542-51. PMC: 3173149. DOI: 10.1074/jbc.M111.271726. View

Kaelin Jr W, Ratcliffe P . Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008; 30(4):393-402. DOI: 10.1016/j.molcel.2008.04.009. View

Seiki M, Yana I . Roles of pericellular proteolysis by membrane type-1 matrix metalloproteinase in cancer invasion and angiogenesis. Cancer Sci. 2003; 94(7):569-74. PMC: 11160244. DOI: 10.1111/j.1349-7006.2003.tb01484.x. View

Hoshino D, Koshikawa N, Suzuki T, Quaranta V, Weaver A, Seiki M . Establishment and validation of computational model for MT1-MMP dependent ECM degradation and intervention strategies. PLoS Comput Biol. 2012; 8(4):e1002479. PMC: 3325185. DOI: 10.1371/journal.pcbi.1002479. View

Brugarolas J, Vazquez F, Reddy A, Sellers W, Kaelin Jr W . TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell. 2003; 4(2):147-58. DOI: 10.1016/s1535-6108(03)00187-9. View

Sakamoto T, Seiki M . Mint3 enhances the activity of hypoxia-inducible factor-1 (HIF-1) in macrophages by suppressing the activity of factor inhibiting HIF-1. J Biol Chem. 2009; 284(44):30350-9. PMC: 2781590. DOI: 10.1074/jbc.M109.019216. View

Iwamoto R, Yamazaki S, Asakura M, Takashima S, Hasuwa H, Miyado K . Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function. Proc Natl Acad Sci U S A. 2003; 100(6):3221-6. PMC: 152273. DOI: 10.1073/pnas.0537588100. View

Urano J, Sato T, Matsuo T, Otsubo Y, Yamamoto M, Tamanoi F . Point mutations in TOR confer Rheb-independent growth in fission yeast and nutrient-independent mammalian TOR signaling in mammalian cells. Proc Natl Acad Sci U S A. 2007; 104(9):3514-9. PMC: 1805553. DOI: 10.1073/pnas.0608510104. View

Wouters B, Koritzinsky M . Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer. 2008; 8(11):851-64. DOI: 10.1038/nrc2501. View

10.

Hudson C, Liu M, Chiang G, Otterness D, Loomis D, Kaper F . Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol. 2002; 22(20):7004-14. PMC: 139825. DOI: 10.1128/MCB.22.20.7004-7014.2002. View

11.

Warburg O . On the origin of cancer cells. Science. 1956; 123(3191):309-14. DOI: 10.1126/science.123.3191.309. View

12.

Laplante M, Sabatini D . mTOR signaling in growth control and disease. Cell. 2012; 149(2):274-93. PMC: 3331679. DOI: 10.1016/j.cell.2012.03.017. View

13.

Huffman T, Mothe-Satney I, Lawrence Jr J . Insulin-stimulated phosphorylation of lipin mediated by the mammalian target of rapamycin. Proc Natl Acad Sci U S A. 2002; 99(2):1047-52. PMC: 117427. DOI: 10.1073/pnas.022634399. View

14.

Mahon P, Hirota K, Semenza G . FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 2001; 15(20):2675-86. PMC: 312814. DOI: 10.1101/gad.924501. View

15.

Pearce L, Komander D, Alessi D . The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol. 2009; 11(1):9-22. DOI: 10.1038/nrm2822. View

16.

Sakamoto T, Seiki M . A membrane protease regulates energy production in macrophages by activating hypoxia-inducible factor-1 via a non-proteolytic mechanism. J Biol Chem. 2010; 285(39):29951-64. PMC: 2943292. DOI: 10.1074/jbc.M110.132704. View

17.

Gatenby R, Gillies R . Why do cancers have high aerobic glycolysis?. Nat Rev Cancer. 2004; 4(11):891-9. DOI: 10.1038/nrc1478. View

18.

Hotary K, Allen E, Brooks P, Datta N, Long M, Weiss S . Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell. 2003; 114(1):33-45. DOI: 10.1016/s0092-8674(03)00513-0. View

19.

Ward P, Thompson C . Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell. 2012; 21(3):297-308. PMC: 3311998. DOI: 10.1016/j.ccr.2012.02.014. View

20.

Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg M, Hall A . Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004; 6(11):1122-8. DOI: 10.1038/ncb1183. View