Regulation of endothelial cell proliferation and vascular assembly through distinct mTORC2 signaling pathways

Molecular and Cellular Biology

Volumn 35, Issue 7, 2015, Pages 1299-1313

  Wang, Shan ^a   Amato, Katherine R ^b   Song, Wenqiang ^a   Youngblood, Victoria ^b   Lee, Keunwook ^b,e   Boothby, Mark ^b   Brantley Sieders, Dana M ^a,c   Chen, Jin ^a,b,c,d  

^a VANDERBILT UNIVERSITY   (United States)

^b VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c VANDERBILT INGRAM CANCER CENTER   (United States)

^d VETERANS AFFAIRS MEDICAL CENTER   (United States)

^e Hallym University   (South Korea)

Author keywords

[No Author keywords available]

Indexed keywords

MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1 SUBUNIT RAPTOR; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2 SUBUNIT RICTOR; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; NDRG1 PROTEIN; PROTEIN KINASE B; PROTEIN KINASE C ALPHA; TAMOXIFEN; UNCLASSIFIED DRUG; VASCULOTROPIN; CARRIER PROTEIN; MULTIPROTEIN COMPLEX; RICTOR PROTEIN, MOUSE; RPTOR PROTEIN, MOUSE; SIGNAL TRANSDUCING ADAPTOR PROTEIN; TARGET OF RAPAMYCIN KINASE; TOR COMPLEX 2; VASCULOTROPIN A;

ANGIOGENESIS; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CAPILLARY ENDOTHELIAL CELL; CELL LYSATE; CELL PROLIFERATION; CONTROLLED STUDY; ENDOTHELIUM CELL; ENZYME SPECIFICITY; ENZYME SUBUNIT; FEMALE; GENE TARGETING; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; LEWIS CARCINOMA; LUNG BLOOD VESSEL; MALE; MOUSE; NONHUMAN; NULL CELL; PRIORITY JOURNAL; PROTEIN DEPLETION; PROTEIN PHOSPHORYLATION; PULMONARY MICROVASCULAR ENDOTHELIAL CELL; SIGNAL TRANSDUCTION; TUMOR GROWTH; TUMOR VASCULARIZATION; UMBILICAL VEIN ENDOTHELIAL CELL; VASCULAR REMODELING; VASCULARIZATION; ANIMAL; CELL CULTURE; CYTOLOGY; GENE DELETION; GENETICS; METABOLISM; PHOSPHORYLATION;

MAMMALIA; MUS; RAPTORES;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; ANIMALS; CARRIER PROTEINS; CELL PROLIFERATION; CELLS, CULTURED; ENDOTHELIAL CELLS; GENE DELETION; HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS; HUMANS; MICE; MULTIPROTEIN COMPLEXES; NEOVASCULARIZATION, PHYSIOLOGIC; PHOSPHORYLATION; PROTEIN KINASE C-ALPHA; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 84924863743     PISSN: 02707306     EISSN: 10985549     Source Type: Journal    
DOI: 10.1128/MCB.00306-14     Document Type: Article

References (50)

1. Potente M, Gerhardt H, Carmeliet P. 2011. Basic and therapeutic aspects of angiogenesis. Cell 146:873-887. http://dx.doi.org/10.1016/j.cell.2011.08.039.
2. Eilken HM, Adams RH. 2010. Dynamics of endothelial cell behavior in sprouting angiogenesis. Curr Opin Cell Biol 22:617-625. http://dx.doi.org/10.1016/j.ceb.2010.08.010.
3. Geudens I, Gerhardt H. 2011. Coordinating cell behaviour during blood vessel formation. Development 138:4569-4583. http://dx.doi.org/10.1242/dev.062323.
4. Zachary I, Gliki G. 2001. Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovasc Res 49:568-581. http://dx.doi.org/10.1016/S0008-6363(00)00268-6.
5. Jiang BH, Liu LZ. 2008. AKT signaling in regulating angiogenesis. Curr Cancer Drug Targets 8:19-26. http://dx.doi.org/10.2174/156800908783497122.
6. Ackah E, Yu J, Zoellner S, Iwakiri Y, Skurk C, Shibata R, Ouchi N, Easton RM, Galasso G, Birnbaum MJ, Walsh K, Sessa WC. 2005. Akt1/protein kinase Balpha is critical for ischemic and VEGF-mediated angiogenesis. J Clin Invest 115:2119-2127. http://dx.doi.org/10.1172/JCI24726.
7. Laplante M, Sabatini DM. 2012. mTOR signaling. Cold Spring Harb Perspect Biol 4:a011593. http://dx.doi.org/10.1101/cshperspect.a011593.
8. Zoncu R, Efeyan A, Sabatini DM. 2011. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12:21-35. http://dx.doi.org/10.1038/nrm3025.
9. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. 2005. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098-1101. http://dx.doi.org/10.1126/science.1106148.
10. Jacinto E, Loewith R, Schmidt A, Lin S, Rüegg MA, Hall A, Hall MN. 2004. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6:1122-1128. http://dx.doi.org/10.1038/ncb1183.
11. Sparks CA, Guertin DA. 2010. Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy. Oncogene 29:3733-3744. http://dx.doi.org/10.1038/onc.2010.139.
12. Phung TL, Ziv K, Dabydeen D, Eyiah-Mensah G, Riveros M, Perruzzi C, Sun J, Monahan-Earley RA, Shiojima I, Nagy JA, Lin MI, Walsh K, Dvorak AM, Briscoe DM, Neeman M, Sessa WC, Dvorak HF, Benjamin LE. 2006. Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell 10:159-170. http://dx.doi.org/10.1016/j.ccr.2006.07.003.
13. Li W, Petrimpol M, Molle KD, Hall MN, Battegay EJ, Humar R. 2007. Hypoxia-induced endothelial proliferation requires both mTORC1 and mTORC2. Circ Res 100:79-87. http://dx.doi.org/10.1161/01.RES.0000253094.03023.3f.
14. Wander SA, Hennessy BT, Slingerland JM. 2011. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J Clin Invest 121:1231-1241. http://dx.doi.org/10.1172/JCI44145.
15. Falcon BL, Barr S, Gokhale PC, Chou J, Fogarty J, Depeille P, Miglarese M, Epstein DM, McDonald DM. 2011. Reduced VEGF production, angiogenesis, and vascular regrowth contribute to the antitumor properties of dual mTORC1/mTORC2 inhibitors. Cancer Res 71:1573-1583. http://dx.doi.org/10.1158/0008-5472.CAN-10-3126.
16. Shiota C, Woo JT, Lindner J, Shelton KD, Magnuson MA. 2006. Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. Dev Cell 11:583-589. http://dx.doi.org/10.1016/j.devcel.2006.08.013.
17. Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM. 2006. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 11:859-871. http://dx.doi.org/10.1016/j.devcel.2006.10.007.
18. Gu Y, Lindner J, Kumar A, Yuan W, Magnuson MA. 2011. Rictor/mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size. Diabetes 60:827-837. http://dx.doi.org/10.2337/db10-1194.
19. Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E, Guertin DA, Madden KL, Carpenter AE, Finck BN, Sabatini DM. 2011. mTORcomplex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146:408-420. http://dx.doi.org/10.1016/j.cell.2011.06.034.
20. Gothert JR, Gustin SE, van Eekelen JA, Schmidt U, Hall MA, Jane SM, Green AR, Gottgens B, Izon DJ, Begley CG. 2004. Genetically tagging endothelial cells in vivo: bone marrow-derived cells do not contribute to tumor endothelium. Blood 104:1769-1777. http://dx.doi.org/10.1182/blood-2003-11-3952.
21. Lindsley CW, Zhao Z, Leister WH, Robinson RG, Barnett SF, Defeo-Jones D, Jones RE, Hartman GD, Huff JR, Huber HE, Duggan ME. 2005. Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. Bioorg Med Chem Lett 15:761-764. http://dx.doi.org/10.1016/j.bmcl.2004.11.011.
22. Brantley-Sieders D, Caughron J, Hicks D, Pozzi A, Ruiz JC, Chen J. 2004. EphA2 receptor tyrosine kinase regulates endothelial cell migration and assembly through phosphoinositide 3-kinase-mediated Rac1 GTPase activation. J Cell Sci 117:2037-2049. http://dx.doi.org/10.1242/jcs.01061.
23. Hunter SG, Zhuang G, Brantley-Sieders DM, Swatt W, Cowan CW, Chen J. 2006. Essential role of Vav family guanine nucleotide exchange factors in EphA receptor-mediated angiogenesis. Mol Cell Biol 26:4830-4842. http://dx.doi.org/10.1128/MCB.02215-05.
24. Fang WB, Brantley-Sieders DM, Hwang Y, Ham AJ, Chen J. 2008. Identification and functional analysis of phosphorylated tyrosine residues within EphA2 receptor tyrosine kinase. J Biol Chem 283:16017-16026. http://dx.doi.org/10.1074/jbc. M709934200.
25. Brantley-Sieders DM, Dunaway CM, Rao M, Short S, Hwang Y, Gao Y, Li D, Jiang A, Shyr Y, Wu JY, Chen J. 2011. Angiocrine factors modulate tumor proliferation and motility through EphA2 repression of Slit2 tumor suppressor function in endothelium. Cancer Res 71:976-987. http://dx.doi.org/10.1158/0008-5472.CAN-10-3396.
26. Martins-Green M, Petreaca M, Yao M. 2008. An assay system for in vitro detection of permeability in human "endothelium." Methods Enzymol 443:137-153. http://dx.doi.org/10.1016/S0076-6879(08)02008-9.
27. Romon R, Adriaenssens E, Lagadec C, Germain E, Hondermarck H, Le Bourhis X. 2010. Nerve growth factor promotes breast cancer angiogenesis by activating multiple pathways. Mol Cancer 9:157. http://dx.doi.org/10.1186/1476-4598-9-157.
28. Brantley-Sieders DM, Fang WB, Hicks DJ, Zhuang G, Shyr Y, Chen J. 2005. Impaired tumor microenvironment in EphA2-deficient mice inhibits tumor angiogenesis and metastatic progression. FASEB J 19:1884-1886. http://dx.doi.org/10.1096/fj.05-4038fje.
29. Brantley-Sieders DM, Zhuang G, Hicks D, Fang WB, Hwang Y, Cates JM, Coffman K, Jackson D, Bruckheimer E, Muraoka-Cook RS, Chen J. 2008. The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling. J Clin Invest 118:64-78. http://dx.doi.org/10.1172/JCI33154.
30. Brantley-Sieders DM, Zhuang G, Vaught D, Freeman T, Hwang Y, Hicks D, Chen J. 2009. Host deficiency in Vav2/3 guanine nucleotide exchange factors impairs tumor growth, survival, and angiogenesis in vivo. Mol Cancer Res 7:615-623. http://dx.doi.org/10.1158/1541-7786.MCR-08-0401.
31. Kohn AD, Takeuchi F, Roth RA. 1996. Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation. J Biol Chem 271:21920-21926. http://dx.doi.org/10.1074/jbc.271.36.21920.
32. Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, Jauch KW, Geissler EK. 2002. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 8:128-135. http://dx.doi.org/10.1038/nm0202-128.
33. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM. 2006. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22:159-168. http://dx.doi.org/10.1016/j.molcel.2006.03.029.
34. Barilli A, Visigalli R, Sala R, Gazzola GC, Parolari A, Tremoli E, Bonomini S, Simon A, Closs EI, Dall'Asta V, Bussolati O. 2008. In human endothelial cells rapamycin causes mTORC2 inhibition and impairs cell viability and function. Cardiovasc Res 78:563-571. http://dx.doi.org/10.1093/cvr/cvn024.
35. Xue Q, Nagy JA, Manseau EJ, Phung TL, Dvorak HF, Benjamin LE. 2009. Rapamycin inhibition of the Akt/mTOR pathway blocks select stages of VEGF-A164-driven angiogenesis, in part by blocking S6Kinase. Arterioscler Thromb Vasc Biol 29:1172-1178. http://dx.doi.org/10.1161/ATVBAHA.109.185918.
36. Zhuang G, Yu K, Jiang Z, Chung A, Yao J, Ha C, Toy K, Soriano R, Haley B, Blackwood E, Sampath D, Bais C, Lill JR, Ferrara N. 2013. Phosphoproteomic analysis implicates the mTORC2-FoxO1 axis in VEGF signaling and feedback activation of receptor tyrosine kinases. Sci Signal 6:ra25. http://dx.doi.org/10.1126/scisignal.2003572.
37. Partovian C, Zhuang Z, Moodie K, Lin M, Ouchi N, Sessa WC, Walsh K, Simons M. 2005. PKCalpha activates eNOS and increases arterial blood flow in vivo. Circ Res 97:482-487. http://dx.doi.org/10.1161/01.RES.0000179775.04114.45.
38. Lee MY, Luciano AK, Ackah E, Rodriguez-Vita J, Bancroft TA, Eichmann A, Simons M, Kyriakides TR, Morales-Ruiz M, Sessa WC. 2014. Endothelial Akt1 mediates angiogenesis by phosphorylating multiple angiogenic substrates. Proc Natl Acad Sci U S A 111:12865-12870. http://dx.doi.org/10.1073/pnas.1408472111.
39. Yuan M, Pino E, Wu L, Kacergis M, Soukas AA. 2012. Identification of Akt-independent regulation of hepatic lipogenesis by mammalian target of rapamycin (mTOR) complex 2. J Biol Chem 287:29579-29588. http://dx.doi.org/10.1074/jbc. M112.386854.
40. Thomanetz V, Angliker N, Cloetta D, Lustenberger RM, Schweighauser M, Oliveri F, Suzuki N, Ruegg MA. 2013. Ablation of the mTORC2 component rictor in brain or Purkinje cells affects size and neuron morphology. J Cell Biol 201:293-308. http://dx.doi.org/10.1083/jcb.201205030.
41. Carson RP, Fu C, Winzenburger P, Ess KC. 2013. Deletion of Rictor in neural progenitor cells reveals contributions of mTORC2 signaling to tuberous sclerosis complex. Hum Mol Genet 22:140-152. http://dx.doi.org/10.1093/hmg/dds414.
42. Janssens V, Longin S, Goris J. 2008. PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail). Trends Biochem Sci 33:113-121. http://dx.doi.org/10.1016/j.tibs.2007.12.004.
43. Westermarck J, Hahn WC. 2008. Multiple pathways regulated by the tumor suppressor PP2A in transformation. Trends Mol Med 14:152-160. http://dx.doi.org/10.1016/j.molmed.2008.02.001.
44. Narasimhan SD, Mukhopadhyay A, Tissenbaum HA. 2009. InAKTivation of insulin/IGF-1 signaling by dephosphorylation. Cell Cycle 8:3878-3884. http://dx.doi.org/10.4161/cc.8.23.10072.
45. Chen CS, Weng SC, Tseng PH, Lin HP, Chen CS. 2005. Histone acetylation-independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase 1 complexes. J Biol Chem 280:38879-38887. http://dx.doi.org/10.1074/jbc. M505733200.
46. Xu W, Yuan X, Jung YJ, Yang Y, Basso A, Rosen N, Chung EJ, Trepel J, Neckers L. 2003. The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells. Cancer Res 63:7777-7784.
47. Li L, Ren CH, Tahir SA, Ren C, Thompson TC. 2003. Caveolin-1 maintains activated Akt in prostate cancer cells through scaffolding domain binding site interactions with and inhibition of serine/threonine protein phosphatases PP1 and PP2A. Mol Cell Biol 23:9389-9404. http://dx.doi.org/10.1128/MCB.23.24.9389-9404.2003.
48. McDonald PC, Oloumi A, Mills J, Dobreva I, Maidan M, Gray V, Wederell ED, Bally MB, Foster LJ, Dedhar S. 2008. Rictor and integrinlinked kinase interact and regulate Akt phosphorylation and cancer cell survival. Cancer Res 68:1618-1624. http://dx.doi.org/10.1158/0008-5472.CAN-07-5869.
49. Agarwal NK, Chen CH, Cho H, Boulbes DR, Spooner E, Sarbassov DD. 2013. Rictor regulates cell migration by suppressing RhoGDI2. Oncogene 32:2521-2526. http://dx.doi.org/10.1038/onc.2012.287.
50. Vilar E, Perez-Garcia J, Tabernero J. 2011. Pushing the envelope in the mTOR pathway: the second generation of inhibitors. Mol Cancer Ther 10:395-403. http://dx.doi.org/10.1158/1535-7163.MCT-10-0905.