Summary
IRS-1 (Insulin Receptor Substrate-1) is an adaptor protein important for insulin and IGF-I receptor (Insulin-like Growth Factor-IR) transduction to downstream targets. One mechanism recently identified to downregulate IGF-I or insulin receptor signaling in diabetic models is IRS-1 Ser312 phosphorylation. To date, the importance of this residue in cancer is unknown. This paper identifies mechanisms leading to Ser312 regulation in MCF-7 breast cancer cells. Whereas IGF-I phosphorylation of IRS312 is PI (phosphatidylinositol) 3-kinase dependent, anisomycin stress treatment requires JNK activation to induce phosphorylation of IRS312. We show that both IGF-I and anisomycin stress treatment converge downstream onto mTOR (Mammalian Target of Rapamycin) and PKCδ (Protein Kinase C-delta) to induce IRS-1 Ser312 phosphorylation. mTOR associates with IRS-1 and is primarily required for Ser312 phosphorylation in response to stress or IGF-I treatment. PKCδ binds to mTOR and its activity is also important for stress or IGF-I mediated Ser312 phosphorylation. Thus, mTOR and PKCδ convey diverse signals to regulate IRS-1 function.
Similar content being viewed by others
References
D Yee (2002) ArticleTitleThe insulin-like growth factor system as a target in breast cancer Semin Oncol 29 86–95 Occurrence Handle10.1053/sonc.2002.34060 Occurrence Handle1:CAS:528:DC%2BD38XmsFWnt78%3D Occurrence Handle12138402
DR Alessi M Andejelkovic B Caudwell P Cron N Morrice P Cohen BA Hemmings (1996) ArticleTitleInsulin and IGF-I EMBO J 15 6541–6551 Occurrence Handle1:CAS:528:DyaK2sXht1Oqs7o%3D Occurrence Handle8978681
B Vanhaesebroack DR Alessi (2000) ArticleTitleThe PI3K-PDK1 connection: more than just a road to PKB Biochem J 346 561–576 Occurrence Handle10.1042/0264-6021:3460561 Occurrence Handle1:CAS:528:DC%2BD3cXit1Kku78%3D Occurrence Handle10698680
JP Peyrat J Bonneterre H Jammes R Beuscart B Hecquet J Djiane J Lefebvre A Demaille (1990) ArticleTitleInsulin-like growth factor 1 receptors (IGF1-R) and IGF1 in human breast tumors J Steroid Biochem and Mol Biol 37 823–827 Occurrence Handle10.1016/0960-0760(90)90426-L Occurrence Handle1:CAS:528:DyaK3MXhtF2msrw%3D
JS Oh JE Kucab PR Bushel K Martin L Bennett J Collins RP DiAugustine JC Barrett CA Afshari SE Dunn (2004) ArticleTitleExpression of the insulin-like growth factor I receptor and urokinase plasminogen activator in breast cancer is associated with poor survival: potential for intervention with 17-allylamino geldanamycin Cancer Research 64 286–291 Occurrence Handle14729636
Y-H Tseng K Ueki KM Kriaucianas CR Kahn (2002) ArticleTitleDifferential roles of insulin receptor substrates in the anti-apoptotic function of insulin-like growth factor-1 and insulin J of Bio Chem 277 31601–31611 Occurrence Handle10.1074/jbc.M202932200 Occurrence Handle1:CAS:528:DC%2BD38XmslOqtrs%3D
AV Lee JL Gooch S Oesterrich RL Guler D Yee (2000) ArticleTitleInsulin-like growth factor-I-induced degradation of insulin receptor substrate 1 is mediated by the 26S proteasome and blocked by phosphatidylinositol 3′-kinase inhibition Mol Cell Biol 20 1489–1496 Occurrence Handle10.1128/MCB.20.5.1489-1496.2000 Occurrence Handle1:CAS:528:DC%2BD3cXhtF2nsbg%3D Occurrence Handle10669726
T Haruta T Uno J Kawahara A Takano K Egawa PM Sharma JM Olefsk M Kobayashi (2000) ArticleTitleA rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1 Mol Endocrinol 14 783–794 Occurrence Handle10.1210/me.14.6.783 Occurrence Handle1:CAS:528:DC%2BD3cXlt1Wgtr8%3D Occurrence Handle10847581
D Hartley GM Cooper (2002) ArticleTitleRole of mTOR in the degradation of IRS-1: regulation of PP2A activity J Cell Biochem 85 304–314 Occurrence Handle10.1002/jcb.10135 Occurrence Handle1:CAS:528:DC%2BD38XivVyqsrg%3D Occurrence Handle11948686
K Paz R Hemi D LeRoith A Karasik E Elhanany H Kanety Y Zick (1997) ArticleTitleA molucular basis for insulin resistance J Biol Chem 272 29911–29918 Occurrence Handle10.1074/jbc.272.47.29911 Occurrence Handle1:CAS:528:DyaK2sXnsFWnsbY%3D Occurrence Handle9368067
K Paz H Voliovitch YR Hadari CT Roberts D LeRoith Y Zick (1996) ArticleTitleInteraction between the insulin receptor and its downstream effectors J Biol Chem 271 6998–7003 Occurrence Handle10.1074/jbc.271.25.15084 Occurrence Handle1:CAS:528:DyaK28XhvVyit7s%3D Occurrence Handle8636129
ME Hartman M Villela-Bach J Chen GG Freund (2001) ArticleTitleFrap-dependent serine phosphorylation of IRS-1 inhibits IRS-1 tyrosine phosphorylation Biochem Biophys Res Commun 280 776–781 Occurrence Handle10.1006/bbrc.2000.4214 Occurrence Handle1:CAS:528:DC%2BD3MXls1aktA%3D%3D Occurrence Handle11162588
V Aguirre ED Werner J Giraud YH Lee SE Schoelson MF White (2002) ArticleTitlePhosporylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action J Biol Chemi 277 1531–1537 Occurrence Handle10.1074/jbc.M101521200 Occurrence Handle1:CAS:528:DC%2BD38XnvFyjtQ%3D%3D
BJ Goldstein A Bittner-Kowalczyk MF White M Harbeck (2000) ArticleTitleTyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein J Biol Chem 276 4283–4289 Occurrence Handle10.1074/jbc.275.6.4283
BT Solow S Harada BJ Goldstein JA Smith MF White L Jarett (1999) ArticleTitleDifferential modulation of the tyrosine phosphorylation state of the insulin receptor by IRS (insulin receptor subunit) proteins Mol Endocrinol 13 1784–1798 Occurrence Handle10.1210/me.13.10.1784 Occurrence Handle1:CAS:528:DyaK1MXms1Omt70%3D Occurrence Handle10517679
K Paz Y.-F Liu H Shorer R Hemi D LeRoith M Quan H Kanety R Seger Y Zick (1999) ArticleTitlePhosphorylation of insulin receptor substrate-1 (IRS-1) by protein kinase B positively regulates IRS-1 function J Biol Chem 274 28816–28822 Occurrence Handle10.1074/jbc.274.40.28816 Occurrence Handle1:CAS:528:DyaK1MXmsFWnsLc%3D Occurrence Handle10497255
V Aguirre T Ucida L Yenush R Davis MF White (2000) ArticleTitleThe c-Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor-1 and phosphorylation of ser307 J␣Biol Chem 275 9047–9054 Occurrence Handle10.1074/jbc.275.12.9047 Occurrence Handle1:CAS:528:DC%2BD3cXit1emt7Y%3D Occurrence Handle10722755
YH Lee J Giraud RJ Davis MF White (2003) ArticleTitlec-Jun N-terminal Kinase (JNK) Mediates Feedback Inhibition of the insulin signaling Cascade J Biol Chem 278 2896–2902 Occurrence Handle10.1074/jbc.M208359200 Occurrence Handle1:CAS:528:DC%2BD3sXmt1Gnuw%3D%3D Occurrence Handle12417588
CL Mamay AM Mingo-Sion DM Wolf MD Molina CL VanDen Berg (2003) ArticleTitleAn inhibitory function for JNK in the regulation of IGF-I signaling in breast cancer Oncogene 22 602–614 Occurrence Handle10.1038/sj.onc.1206186 Occurrence Handle1:CAS:528:DC%2BD3sXmslGksQ%3D%3D Occurrence Handle12555073
MW Greene H Sakaue L Wang DR Alessi RA Roth (2003) ArticleTitleModulation of insulin-stimulated degradation of human insulin receptor substrate-1 by serine 312 phosphorylation J Biol Chem 278 8199–8211 Occurrence Handle10.1074/jbc.M209153200 Occurrence Handle1:CAS:528:DC%2BD3sXhsF2hsrs%3D Occurrence Handle12510059
K De Fea RA Roth (1997) ArticleTitleModulation of insulin receptor substrate-1 tyrosine phosphorylation and function by mitogen-activated protein kinase J Biol Chem 272 31400–31406 Occurrence Handle10.1074/jbc.272.50.31400 Occurrence Handle1:CAS:528:DyaK2sXotVSks7g%3D Occurrence Handle9395471
MW Greene N Morrice RS Garofalo RA Roth (2004) ArticleTitleModulation of human insulin receptor substrate-1 phosphorylation by protein kinase Cδ Biochem J 378 105–116 Occurrence Handle1:CAS:528:DC%2BD2cXitlSnsr8%3D Occurrence Handle14583092
Z Gao D Hwang F Bataille M Lefevre D York MJ Quon J Ye (2002) ArticleTitleSerine Phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex J Biol Chem 277 48115–48121 Occurrence Handle1:CAS:528:DC%2BD38Xptlegsr4%3D Occurrence Handle12351658
L Rui V Aguirre JK Kim GI Shulman A Lee A Corbould A Dunaif MF White (2001) ArticleTitleInsulin/IGF-1 and TNF-α stimulates phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways J Clin Invest 107 181–189 Occurrence Handle1:CAS:528:DC%2BD3MXkvVChsA%3D%3D Occurrence Handle11160134
PH Scott GJ Brunn AD Kohn RA Roth JC Lawrence (1998) ArticleTitleEvidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by protein kinase B signaling pathway Proceedings of the National Academy of Science of the United States of America 95 7772–7777 Occurrence Handle1:CAS:528:DyaK1cXktFCgsLs%3D
A Sekulic CC Hudson JL Homme P Yin DM Otterness LM Karnitz RT Abraham (2000) ArticleTitleA direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells Cancer Res 60 3504–3513 Occurrence Handle1:CAS:528:DC%2BD3cXkvFChsL0%3D Occurrence Handle10910062
PE Burnett RK Barrow NA Cohen SH Snyder DM Sabatini (1998) ArticleTitleRAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1 Proc Nat Acad Sci 95 1432–1437 Occurrence Handle1:CAS:528:DyaK1cXht1Wqsbo%3D Occurrence Handle9465032
LP McMahon KM Choi T-A Lin RT Abraham JC Lawrence (2002) ArticleTitleThe rapamycin-binding domain governs substrate selectivity by the mammalian target of rapamycin Mol Cell Biol 22 7428–7437 Occurrence Handle1:CAS:528:DC%2BD38XotVKhs7c%3D Occurrence Handle12370290
D Parekh W Ziegler K Yonezawa K Hara PJ Parker (1999) ArticleTitleMammalian TOR controls one of two kinase pathways acting upon nPKCδ and nPKCɛ J Biol Chem 274 34758–34763 Occurrence Handle1:CAS:528:DyaK1MXnvFyrsLo%3D Occurrence Handle10574945
J Srivastava J Goris SM Dilworth PJ Parker (2002) ArticleTitleDephosphorylation of PKCδ by protein phosphatase 2Ac and its inhibition by nucleotides FEBS Lett 516 265–269 Occurrence Handle1:CAS:528:DC%2BD38XivVaiur4%3D Occurrence Handle11959144
JA Le Good W Ziegler D Parekh DR Alessi P Cohen PJ Parker (1998) ArticleTitleProtein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1 Science 281 2042–2045 Occurrence Handle1:CAS:528:DyaK1cXmtlKlsbg%3D Occurrence Handle9748166
V Kumar P Pandey D Sabatini M Kumar PK Majumder A Bharti G Carmichael D Kufe S Kharbanda (2000) ArticleTitleFunctional interaction between RAFT1/FARP/mTOR and protein kinase Cδ in the regulation of cap-dependent initiation of translation EMBO J 19 1087–1097 Occurrence Handle1:CAS:528:DC%2BD3cXitVyrs7k%3D Occurrence Handle10698949
del Rincon, SV, Guo, Q, Morelli, C, Shiu, H-Y, Surmacz, E, and Miller, WH Retinoic acid mediates degradation of IRS-1 by the ubiquitin-proteosome pathway, via a PKC-dependent mechanism. Oncogene, 1–11. 2004
O Potapova M Gorospe F Bost NM Dean WA Gaarde D Mercola NJ Holbrook (2000) ArticleTitlec-Jun N-terminal kinase is for growth of human T98G glioblastoma cells J Biol Chem 275 24767–24775 Occurrence Handle1:CAS:528:DC%2BD3cXlsl2jtrg%3D Occurrence Handle10825181
TF Franke S-I Yang TO Chan K Datta A Kaziauskas DK Morrison DR Kaplan PN Tsichlis (1995) ArticleTitleThe protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase Cell 81 727–736 Occurrence Handle1:CAS:528:DyaK2MXmtFOiur8%3D Occurrence Handle7774014
M Hibi A Lin T Smeal A Minden M Karin (1993) ArticleTitleIdentification of an oncoprotein- and UV-responsive protein kinase that bind and potentiate the c-Jun activation domain Genes Dev 7 2135–2148 Occurrence Handle1:CAS:528:DyaK2cXisVyksQ%3D%3D Occurrence Handle8224842
BL Bennett DT Sasaki BW Murray EC O’Leary ST Sakata W Xu JC Leisten A Motiwala S Pierce Y Satoh SS Bhagwat AM Manning DW Anderson (2001) ArticleTitleSP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase Proc Nat Acad Sci USA 98 13681–13686 Occurrence Handle1:CAS:528:DC%2BD3MXovVynsbg%3D Occurrence Handle11717429
M Barlund F Forozan J Kononen (2000) ArticleTitleDetecting activation of ribosomal protein S6 kinase by complementary DNA and tissue microarray analysis J Nat Cancer Inst 92 1252–1259 Occurrence Handle1:CAS:528:DC%2BD3cXlvFyhsb0%3D Occurrence Handle10922410
VI Shifrin P Anderson (1999) ArticleTitleTrichothecene mycotoxins trigger a ribotoxic stress response that activates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase and induces apoptosis J Biol Chem 274 13985–13992 Occurrence Handle1:CAS:528:DyaK1MXjsFWqsrw%3D Occurrence Handle10318810
H-Y Lee H Srinivas D Xia Y Lu R Superty R LaPushin C Gomez-Manzano AM Gal GL Walsh T Force K Ueki GB Mills JM Kurie (2003) ArticleTitleEvidence that phosphatidylinositol 3-kinase- and mitogen-activated protein kinase kinase-4/c-Jun NH2-terminal kinase-dependent pathways cooperate to maintain lung cancer cell survival J Biol Chem 278 23630–23638 Occurrence Handle1:CAS:528:DC%2BD3sXkslygt70%3D Occurrence Handle12714585
SA Molton DE Todd SJ Cook (2003) ArticleTitleSelective activation of c-Jun N-terminal kinase (JNK) pathway fails to elicit Bax activation or apoptosis unless the phosphoinositide 3′-kinase (PI3K) pathway is inhibited Oncogene 22 4690–4701 Occurrence Handle1:CAS:528:DC%2BD3sXls1Gjtb8%3D Occurrence Handle12879014
C Brodie PM Blumberg (2003) ArticleTitleRegulation of cell apoptosis by protein kinase c δ Apoptosis 8 19–27 Occurrence Handle1:CAS:528:DC%2BD38XpsFyjurY%3D Occurrence Handle12510148
V Kumar D Sabatini P Pandey A-C Gingras PK Majumder M Kumar Z-M Yuan G Carmichael R Weichselbaum N Sonenberg D Kufe S Kharbanda (2000) ArticleTitleRegulation of the rapamycin and FKBP-target 1/mammalian target of rapamcyin and cap-dependent initiation of translation by the c-Abl protein tyrosine kinase J Biol Chem 275 10779–10787 Occurrence Handle1:CAS:528:DC%2BD3cXislShsrY%3D Occurrence Handle10753870
SC Kiley KJ Clark SK Duddy DR Welch S Jaken (1999) ArticleTitleIncreased protein kinase Cδ in mammary tumor cells: relationship to transformation and metastatic progression Oncogene 18 6748–6757 Occurrence Handle10.1038/sj.onc.1203101 Occurrence Handle1:CAS:528:DyaK1MXotV2lsr8%3D Occurrence Handle10597283
SC Kiley KJ Clark M Goodnough DR Welch S Jaken (1999) ArticleTitleProtein Kinase C δ involvement in mammary tumor cell metastasis Cancer Res 59 3230–3238 Occurrence Handle1:CAS:528:DyaK1MXksVGjsrk%3D Occurrence Handle10397270
H Kaneto Y Nakatani T Miyatsuka D Kawamori T Matsuoka M Matsuhisa Y Kajimoto H Ichiijo M Hori (2004) ArticleTitlePossible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide Nat Med 10 1128–1132 Occurrence Handle1:CAS:528:DC%2BD2cXnvFyntbg%3D Occurrence Handle15448687
J Hirosumi G Tuncman L Chang CZ Gorgun KT Uysal K Maeda M Karin GS Hotamisligil (2002) ArticleTitleA central role for JNK in obesity and insulin resistance Nature(London) 420 333–336 Occurrence Handle1:CAS:528:DC%2BD38XovVekt7g%3D
A Jaeschke MP Czech RJ Davis (2004) ArticleTitleAn essential role of the JIP1 scaffold protein for JNK activation in adipose tissue Genes Dev 18 1976–1980 Occurrence Handle1:CAS:528:DC%2BD2cXmvFKqsb0%3D Occurrence Handle15314024
ED Werner J Lee L Hansen M Yuan SE Shoelson (2004) ArticleTitleInsulin resistance due to phosphorylation of Insulin Receptor Substrate-1 at serine 302 J Biol Chem 279 35298–35305 Occurrence Handle1:CAS:528:DC%2BD2cXmsl2iurk%3D Occurrence Handle15199052
LS Harrington GM Findlay A Gray T Tolkacheva S Wigfield H Rebholz J Barnett NR Leslie S Cheng PR Shepherd I Gout P Downes RF Lamb (2004) ArticleTitleThe TSC1–2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins J Cell Biol 166 213–223 Occurrence Handle1:CAS:528:DC%2BD2cXlvFKqsrw%3D Occurrence Handle15249583
CJ Carlson MF White CM Rondinone (2004) ArticleTitleMammalian target of rapamycin regulates IRS-1 serine 307 phosphorylation Biochem Biophys Res Commun 316 533–539 Occurrence Handle1:CAS:528:DC%2BD2cXitFKhu7o%3D Occurrence Handle15020250
SE Dunn RA Hardman FW Kari JC Barrett (1997) ArticleTitleInsulin-like growth factor-1 (IGF-1) alters drug sensitivity of HBL100 human breast cancer cells by inhibition of apoptosis induced diverse anticancer drugs Cancer Res 57 2687–2693 Occurrence Handle1:CAS:528:DyaK2sXktlSis7s%3D Occurrence Handle9205078
JL Gooch CL VanDen Berg D Yee (1999) ArticleTitleInsulin-like growth factor (IGF)-I rescues breast cancer cells from chemotherapy-induced cell death- proliferative and anti-apoptotic effects Breast Cancer Res Treat 56 1–10 Occurrence Handle1:CAS:528:DyaK1MXmvVyns7s%3D Occurrence Handle10517338
S Huang PJ Houghton (2003) ArticleTitleTargeting mTOR signaling for cancer therapy Current Opinions in Pharmacol 3 1–7
M Hidalgo EK Rowinsky (2000) ArticleTitleThe rapamycin-sensitive signal transduction pathway as a target for cancer therapy Oncogene 19 6680–6686 Occurrence Handle1:CAS:528:DC%2BD3MXhsF2rs7w%3D Occurrence Handle11426655
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mingo-Sion, A.M., Ferguson, H.A., Koller, E. et al. PKCδ and mTOR interact to regulate stress and IGF-I induced IRS-1 Ser312 phosphorylation in breast cancer cells. Breast Cancer Res Treat 91, 259–269 (2005). https://doi.org/10.1007/s10549-005-0669-0
Issue Date:
DOI: https://doi.org/10.1007/s10549-005-0669-0