title: PI3K/Akt-sensitive MEK-independent compensatory circuit of ERK activation in ER-positive PI3K-mutant T47D breast cancer cells.
abstract: We explored the crosstalk between cell survival (phosphatidylinositol 3-kinase (PI3K)/Akt) and mitogenic (Ras/Raf/MEK/extracellular signal-regulated kinase (ERK)) signaling pathways activated by an epidermal growth factor (EGF) and analyzed their sensitivity to small molecule inhibitors in the PI3K-mutant estrogen receptor (ER)-positive MCF7 and T47D breast cancer cells. In contrast to MCF7 cells, ERK phosphorylation in T47D cells displayed resistance to MEK inhibition by several structurally different compounds, such as U0126, PD 098059 and PD 198306, MEK suppression by small interfering RNA (siRNA) and was also less sensitive to PI3K inhibition by wortmannin. Similar effect was observed in PI3K-wild type ER-positive BT-474 cells, albeit to a much lesser extent. MEK-independent ERK activation was induced only by ErbB receptor ligands and was resistant to inhibition of several kinases and phosphatases that are known to participate in the regulation of Ras/mitogen-activated protein kinase (MAPK) cascade. Although single agents against PDK1 or Akt did not affect EGF-induced ERK phosphorylation, a combination of PI3K/Akt and MEK inhibitors synergistically suppressed ERK activation and cellular growth. siRNA-mediated silencing of class I PI3K or Akt1/2 genes also significantly decreased U0126-resistant ERK phosphorylation. Our data suggest that in T47D cells ErbB family ligands induce a dynamic, PI3K/Akt-sensitive and MEK-independent compensatory ERK activation circuit that is absent in MCF7 cells. We discuss candidate proteins that can be involved in this activation circuitry and suggest that PDZ-Binding Kinase/T-LAK Cell-Originated Protein Kinase (PBK/TOPK) may play a role in mediating MEK-independent ERK activation.
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust St., Philadelphia, PA 19107, USA.
authors.forename: Edita
authors.initials: E
authors.lastname: Aksamitiene
authors.forename: Boris N
authors.initials: BN
authors.lastname: Kholodenko
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
authors.forename: Jan B
authors.initials: JB
authors.lastname: Hoek
authors.forename: Anatoly
authors.initials: A
authors.lastname: Kiyatkin
mesh_terms: D001943:Breast Neoplasms / Q000737:chemistry / Q000201:enzymology*; D018270:Carcinoma, Ductal, Breast / Q000737:chemistry / Q000201:enzymology*; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000032:analysis
chemical_list: D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D036341:Intercellular Signaling Peptides and Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011960:Receptors, Estrogen; C409022:PDZ-binding kinase
references.citation: J Am Soc Nephrol. 2008 Feb;19(2):380-7
references.pmid: 18184861
references.citation: Cancer Res. 2009 Jan 15;69(2):565-72
references.pmid: 19147570
references.citation: J Biol Chem. 1995 Jul 14;270(28):16483-6
references.pmid: 7622446
references.citation: Cell Signal. 2005 Mar;17(3):341-53
references.pmid: 15567065
references.citation: J Biol Chem. 2002 May 31;277(22):19382-8
references.pmid: 11896055
references.citation: Breast Cancer Res. 2001;3(6):385-9
references.pmid: 11737890
references.citation: Semin Cell Dev Biol. 2004 Apr;15(2):161-70
references.pmid: 15209375
references.citation: BMC Neurosci. 2009 Jul 14;10:74
references.pmid: 19602257
references.citation: Nat Rev Drug Discov. 2009 Sep;8(9):709-23
references.pmid: 19629074
references.citation: Biochem Biophys Res Commun. 2004 Dec 17;325(3):997-1004
references.pmid: 15541388
references.citation: Methods Mol Biol. 2009;536:149-61
references.pmid: 19378054
references.citation: J Clin Endocrinol Metab. 2007 Dec;92(12):4686-95
references.pmid: 17911174
references.citation: Cancer Res. 2006 Sep 15;66(18):9186-95
references.pmid: 16982762
references.citation: FEBS Lett. 2001 Jul 27;502(1-2):21-4
references.pmid: 11478941
references.citation: J Biol Chem. 2002 Jul 12;277(28):24967-75
references.pmid: 11994282
references.citation: Genomics. 2003 Feb;81(2):112-25
references.pmid: 12620389
references.citation: Oncogene. 2000 May 15;19(21):2474-88
references.pmid: 10851046
references.citation: Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37
references.pmid: 11252954
references.citation: Int J Oncol. 2008 Oct;33(4):791-8
references.pmid: 18813793
references.citation: J Biol Chem. 1998 Jan 16;273(3):1496-505
references.pmid: 9430688
references.citation: Int J Mol Med. 2000 Aug;6(2):155-60
references.pmid: 10891559
references.citation: Biochem Biophys Res Commun. 2002 Apr 26;293(1):463-9
references.pmid: 12054624
references.citation: J Mammary Gland Biol Neoplasia. 2000 Jul;5(3):271-81
references.pmid: 14973389
references.citation: Breast Cancer Res Treat. 2004 Jul;86(2):139-52
references.pmid: 15319566
references.citation: Am J Pathol. 2001 Feb;158(2):639-46
references.pmid: 11159200
references.citation: Mol Cell Biol. 2005 Jul;25(13):5725-37
references.pmid: 15964826
references.citation: FEBS Lett. 2002 Jun 19;521(1-3):157-64
references.pmid: 12067709
references.citation: J Ocul Pharmacol Ther. 2006 Apr;22(2):93-102
references.pmid: 16722795
references.citation: J Mol Endocrinol. 2008 Apr;40(4):173-84
references.pmid: 18372406
references.citation: Cancer Cell. 2008 Jan;13(1):36-47
references.pmid: 18167338
references.citation: Proc Natl Acad Sci U S A. 2008 May 13;105(19):6870-5
references.pmid: 18463290
references.citation: Exp Cell Res. 2003 Mar 10;284(1):89-98
references.pmid: 12648468
references.citation: J Pharmacol Exp Ther. 2009 Jun;329(3):1063-70
references.pmid: 19258520
references.citation: Mol Cancer Res. 2007 Feb;5(2):195-201
references.pmid: 17314276
references.citation: Oncogene. 2000 Dec 7;19(52):6074-81
references.pmid: 11146560
references.citation: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5167-72
references.pmid: 10779557
references.citation: J Cell Sci. 2002 Apr 15;115(Pt 8):1575-81
references.pmid: 11950876
references.citation: Mol Syst Biol. 2009;5:256
references.pmid: 19357636
references.citation: Nat Med. 2006 Nov;12(11):1294-300
references.pmid: 17057710
references.citation: J Cell Biol. 2002 Jan 7;156(1):65-74
references.pmid: 11777941
references.citation: J Cell Biol. 2000 Jan 24;148(2):385-97
references.pmid: 10648571
references.citation: J Clin Endocrinol Metab. 2008 Jun;93(6):2194-201
references.pmid: 18381570
references.citation: Gastroenterology. 2007 Jul;133(1):219-31
references.pmid: 17631144
references.citation: Clin Cancer Res. 2009 Jul 15;15(14):4649-64
references.pmid: 19567590
references.citation: J Biol Chem. 2004 Oct 22;279(43):44513-21
references.pmid: 15316018
references.citation: J Cell Physiol. 2005 Aug;204(2):437-44
references.pmid: 15672448
references.citation: J Biol Chem. 1999 Nov 19;274(47):33684-90
references.pmid: 10559258
references.citation: J Biol Chem. 2001 Nov 23;276(47):43871-8
references.pmid: 11571286
references.citation: FEBS Lett. 2001 Mar 9;492(1-2):39-44
references.pmid: 11248233
references.citation: PLoS Comput Biol. 2008 Feb 29;4(2):e1000013
references.pmid: 18463697
references.citation: J Biol Chem. 2006 Jul 21;281(29):19925-38
references.pmid: 16687399
references.citation: Bioorg Med Chem Lett. 1998 Oct 20;8(20):2839-44
references.pmid: 9873633
references.citation: J Biol Chem. 2001 Mar 23;276(12):9166-73
references.pmid: 11118451
references.citation: J Biol Chem. 2004 Oct 15;279(42):43861-9
references.pmid: 15284233
references.citation: Exp Cell Res. 2003 Mar 10;284(1):31-53
references.pmid: 12648464