Matrix Adhesion and Ras Transformation Both Activate a Phosphoinositide 3-OH Kinase and Protein Kinase B/Akt Cellular Survival Pathway

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 1997 May 15

PMID 9184223

Citations 265

Authors

A Khwaja

P Rodriguez-Viciana

S Wennstrom

P H Warne

J Downward

Affiliations

Soon will be listed here.

Abstract

Upon detachment from the extracellular matrix, epithelial cells enter into programmed cell death, a phenomenon known as anoikis, ensuring that they are unable to survive in an inappropriate location. Activated ras oncogenes protect cells from this form of apoptosis. The nature of the survival signals activated by integrin engagement and usurped by oncogenic Ras are unknown: here we show that in both cases phosphoinositide 3-OH kinase (PI 3-kinase), but not Raf, mediates this protection, acting through protein kinase B/Akt (PKB/Akt). Constitutively activated PI 3-kinase or PKB/Akt block anoikis, while inhibition of PI 3-kinase abrogates protection by Ras, but not PKB/Akt. Inhibition of either PI 3-kinase or PKB/Akt induces apoptosis in adherent epithelial cells. Attachment of cells to matrix leads to rapid elevation of the levels of PI 3-kinase lipid products and PKB/Akt activity, both of which remain high in Ras-transformed cells even in suspension. PI 3-kinase acting through PKB/Akt is therefore implicated as a key mediator of the aberrant survival of Ras-transformed epithelial cells in the absence of attachment, and mediates matrix-induced survival of normal epithelial cells.

Citing Articles

Ameliorative Effect of Ginsenoside Rc on 5-Fluorouracil-Induced Chemotherapeutic Intestinal Mucositis via the PI3K-AKT/NF-κB Signaling Pathway: In Vivo and In Vitro Evaluations.

Xu L, Zhao X, Tang F, Zhang J, Peng C, Ao H Int J Mol Sci. 2024; 25(23).

PMID: 39684797 PMC: 11642520. DOI: 10.3390/ijms252313085.

A comprehensive review of stroke-related signaling pathways and treatment in western medicine and traditional Chinese medicine.

Chen B, Jin W Front Neurosci. 2023; 17:1200061.

PMID: 37351420 PMC: 10282194. DOI: 10.3389/fnins.2023.1200061.

A novel anoikis-related gene prognostic signature and its correlation with the immune microenvironment in colorectal cancer.

Xiao Y, Zhou H, Chen Y, Liu L, Wu Q, Li H Front Genet. 2023; 14:1186862.

PMID: 37323657 PMC: 10265740. DOI: 10.3389/fgene.2023.1186862.

Therapeutic targeting of anoikis resistance in cutaneous melanoma metastasis.

Neuendorf H, Simmons J, Boyle G Front Cell Dev Biol. 2023; 11:1183328.

PMID: 37181747 PMC: 10169659. DOI: 10.3389/fcell.2023.1183328.

Receptor binding domain of SARS-CoV-2 is a functional αv-integrin agonist.

Norris E, Pan X, Hocking D bioRxiv. 2022; .

PMID: 35441172 PMC: 9016641. DOI: 10.1101/2022.04.11.487882.

References

Stoker M, ONeill C, Berryman S, Waxman V . Anchorage and growth regulation in normal and virus-transformed cells. Int J Cancer. 1968; 3(5):683-93. DOI: 10.1002/ijc.2910030517. View

Hawkins P, Eguinoa A, Qiu R, Stokoe D, Cooke F, Walters R . PDGF stimulates an increase in GTP-Rac via activation of phosphoinositide 3-kinase. Curr Biol. 1995; 5(4):393-403. DOI: 10.1016/s0960-9822(95)00080-7. View

Krengel U, Schlichting I, Scherer A, Schumann R, Frech M, John J . Three-dimensional structures of H-ras p21 mutants: molecular basis for their inability to function as signal switch molecules. Cell. 1990; 62(3):539-48. DOI: 10.1016/0092-8674(90)90018-a. View

Bellacosa A, Testa J, Staal S, Tsichlis P . A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Science. 1991; 254(5029):274-7. DOI: 10.1126/science.254.5029.274. View

Leevers S, Marshall C . Activation of extracellular signal-regulated kinase, ERK2, by p21ras oncoprotein. EMBO J. 1992; 11(2):569-74. PMC: 556488. DOI: 10.1002/j.1460-2075.1992.tb05088.x. View

Schweighoffer F, Barlat I, Tocque B . Implication of GAP in Ras-dependent transactivation of a polyoma enhancer sequence. Science. 1992; 256(5058):825-7. DOI: 10.1126/science.1317056. View

Price D, Grove J, Calvo V, Avruch J, Bierer B . Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. Science. 1992; 257(5072):973-7. DOI: 10.1126/science.1380182. View

Nakanishi H, Brewer K, EXTON J . Activation of the zeta isozyme of protein kinase C by phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1993; 268(1):13-6. View

Meredith Jr J, Fazeli B, Schwartz M . The extracellular matrix as a cell survival factor. Mol Biol Cell. 1993; 4(9):953-61. PMC: 275725. DOI: 10.1091/mbc.4.9.953. View

10.

Vlahos C, Matter W, Hui K, Brown R . A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem. 1994; 269(7):5241-8. View

11.

Frisch S, Francis H . Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol. 1994; 124(4):619-26. PMC: 2119917. DOI: 10.1083/jcb.124.4.619. View

12.

Marshall C . MAP kinase kinase kinase, MAP kinase kinase and MAP kinase. Curr Opin Genet Dev. 1994; 4(1):82-9. DOI: 10.1016/0959-437x(94)90095-7. View

13.

Kotani K, Yonezawa K, Hara K, Ueda H, Kitamura Y, Sakaue H . Involvement of phosphoinositide 3-kinase in insulin- or IGF-1-induced membrane ruffling. EMBO J. 1994; 13(10):2313-21. PMC: 395096. DOI: 10.1002/j.1460-2075.1994.tb06515.x. View

14.

Cowley S, PATERSON H, Kemp P, Marshall C . Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell. 1994; 77(6):841-52. DOI: 10.1016/0092-8674(94)90133-3. View

15.

Chung J, Grammer T, Lemon K, Kazlauskas A, Blenis J . PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase. Nature. 1994; 370(6484):71-5. DOI: 10.1038/370071a0. View

16.

Ming X, Burgering B, Wennstrom S, Claesson-Welsh L, Heldin C, Bos J . Activation of p70/p85 S6 kinase by a pathway independent of p21ras. Nature. 1994; 371(6496):426-9. DOI: 10.1038/371426a0. View

17.

Chen Q, Kinch M, Lin T, Burridge K, Juliano R . Integrin-mediated cell adhesion activates mitogen-activated protein kinases. J Biol Chem. 1994; 269(43):26602-5. View

18.

Kikuchi A, Demo S, Ye Z, Chen Y, Williams L . ralGDS family members interact with the effector loop of ras p21. Mol Cell Biol. 1994; 14(11):7483-91. PMC: 359284. DOI: 10.1128/mcb.14.11.7483-7491.1994. View

19.

Chen H, Guan J . Association of focal adhesion kinase with its potential substrate phosphatidylinositol 3-kinase. Proc Natl Acad Sci U S A. 1994; 91(21):10148-52. PMC: 44975. DOI: 10.1073/pnas.91.21.10148. View

20.

Chong L, Bokoch G, Schwartz M . The small GTP-binding protein Rho regulates a phosphatidylinositol 4-phosphate 5-kinase in mammalian cells. Cell. 1994; 79(3):507-13. DOI: 10.1016/0092-8674(94)90259-3. View