Error message

No crossref credentials set for pnas

Phosphoinositide 3-kinase regulatory subunit p85α suppresses insulin action via positive regulation of PTEN

PNAS, 8 August 2006
Vol. 103, Issue 32, p. 12093-12097
DOI: 10.1073/pnas.0604628103

Phosphoinositide 3-kinase regulatory subunit p85α suppresses insulin action via positive regulation of PTEN

  1. Cullen M. Taniguchi *,
  2. Thien T. Tran *,
  3. Tatsuya Kondo ,
  4. Ji Luo , § ,
  5. Kohjiro Ueki ,
  6. Lewis C. Cantley , § , , and
  7. C. Ronald Kahn * , **
  1. *Cellular and Molecular Physiology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215;
  2. Department of Metabolic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8555, Japan;
  3. Department of Systems Biology, Harvard Medical School, Boston, MA 02215;
  4. §Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115; and
  5. Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan
  1. Contributed by Lewis C. Cantley, June 3, 2006

  1. Fig. 1.

    Metabolic phenotype of L-Pik3r1KO mice. (A) Western blots for Pik3r1 gene products with an antibody against the N-terminal SH2 domain (pan-p85) in tissue lysates, as indicated, from control, heterozygous KO, and L-Pik3r1KO mice. Tissues were collected from mice after an overnight fast, and proteins were extracted and processed as described in Materials and Methods. Each lane represents lysates from a different mouse. (B and C) Fasted blood glucose and fasted serum insulin levels. (D and E) Serum triglycerides and serum nonesterified free fatty acid (FFA) levels from lox/lox or KO mice in the fasted state. (F) Glucose tolerance tests (2 g/kg, i.p.) were performed on mice after a 16-h fast, and blood samples were collected and glucose measured at the times indicated. All values are presented as mean ± SEM (n = 6–20). Open circles, lox/lox; filled circles, L-Pik3r1KO.

  2. Fig. 2.

    Hyperinsulinemic–euglycemic clamp analyses and gene expression changes in lox/lox (WT) and L-Pik3r1KO mice. We subjected male mice (n = 11) of the indicated genotype at 10–12 weeks of age to hyperinsulinemic–euglycemic clamp analysis and measured insulin suppression of HGP (A), glucose infusion rates (B), and in vivo 14C-deoxyglucose uptake in muscle (C) and epididymal fat tissue (D). (E and F) Weight of entire animals or of epididymal (WAT) and brown (BAT) fat pads. WAT and BAT are expressed as a percentage of body weight. (G) Quantitative RT-PCR analysis of mRNA levels in lox/lox and L-Pik3r1KO mice of phosphoenolpyruvate carboxykinase (Pck1), glucose-6-phosphatase (G6Pc), fructose-1,6-bisphosphatase (Fbp1), peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (Ppargc1), tribbles3 (trib3), and glucokinase (Gck1). n = 8 for each genotype for RT-PCR experiments. ∗, P < 0.05 vs. lox/lox mice.

  3. Fig. 3.

    Enhanced Akt activation in L-Pik3r1KO mice. (A) PI3K activity in IRS-1, IRS-2, and pTyr immunoprecipitates (bars represent mean ± SEM; n = 5; ∗, P < 0.05). (B and C) Western blot of p110α and p85α from p110α immunoprecipitates and pTyr and insulin receptor (IR) blots from insulin receptor (β-subunit) immunoprecipitates. (D) Ser-473 phosphorylation of Akt (Upper) and Akt kinase activity as measured from Akt immunoprecipitates by using Crosstide as a substrate (Lower). Bars represent mean ± SEM; n = 8; ∗, P < 0.05 vs. insulin-stimulated lox/lox mice.

  4. Fig. 4.

    Enhanced PIP3 levels in L-Pik3r1KO mice due to decreased PTEN activity. (A) Immunofluorescent staining with a primary anti-PIP3 antibody (IgM) and an anti-mouse secondary antibody conjugated to Alexa Fluor red and counterstained with DAPI. After an overnight fast, mice were injected with saline (time = 0) or 5 units of insulin for the indicated amount of time. Six mice of each genotype/treatment were fixed via cardiac perfusion of 10% buffered formalin in PBS. (B) Quantification of the immunofluorescence from PIP3 staining. Representative slides were chosen from each mouse, and the fluorescence intensity was measured and analyzed with vh-h1a5 analyzer software (KEYENCE, Osaka, Japan). (C and D) Insulin-stimulated pTyr-associated PI3K activity and PTEN activity and PTEN protein levels in lox/lox or KO animals at the indicated time points after insulin stimulation. ∗, P < 0.05 vs. lox/lox after 5 min of insulin stimulation.


  • To whom correspondence may be addressed. E-mail: lcantley{at}
  • **To whom correspondence may be addressed at:
    Joslin Diabetes Center, One Joslin Place, Boston, MA 02215.
    E-mail: c.ronald.kahn{at}


C. M. Taniguchi, T. T. Tran, T. Kondo, J. Luo, K. Ueki, L. C. Cantley, and C. R. Kahn, Phosphoinositide 3-kinase regulatory subunit p85α suppresses insulin action via positive regulation of PTEN. PNAS 103, 12093-12097 (2006).

Uncovering the PI3Ksome: Phosphoinositide 3-Kinases and Counteracting PTEN Form a Signaling Complex with Intrinsic Regulatory Properties
C. Conche, and K. Sauer
Mol. Cell. Biol. 34, 3356-3358 (15 September 2014)

Cell Activation-Induced Phosphoinositide 3-Kinase Alpha/Beta Dimerization Regulates PTEN Activity
V. Perez-Garcia, J. Redondo-Munoz, A. Kumar, and A. C. Carrera
Mol. Cell. Biol. 34, 3359-3373 (15 September 2014)

Human Placental Lactogen Induces CYP2E1 Expression via PI 3-Kinase Pathway in Female Human Hepatocytes
J. K. Lee, H. J. Chung, L. Fischer, J. Fischer, F. J. Gonzalez, and H. Jeong
Drug Metab. Dispos. 42, 492-499 (1 April 2014)

Insulin Receptor Signaling in Normal and Insulin-Resistant States
J. Boucher, A. Kleinridders, and C. R. Kahn
Cold Spring Harb. Perspect. Biol. 6, a009191-a009191 (1 January 2014)

Pioglitazone does not improve insulin signaling in mice with GH over-expression
A. Gesing, A. Bartke, and M. M. Masternak
J Endocrinol 219, 109-117 (4 October 2013)

The p110{alpha} and p110{beta} isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis
T. Utermark, T. Rao, H. Cheng, Q. Wang, S. H. Lee, Z. C. Wang, J. D. Iglehart, T. M. Roberts, W. J. Muller, J. J. Zhao et al.
Genes Dev. 26, 1573-1586 (15 July 2012)

Calorie restriction and rapamycin inhibit MMTV-Wnt-1 mammary tumor growth in a mouse model of postmenopausal obesity
L. M. Nogueira, S. M. Dunlap, N. A. Ford, and S. D. Hursting
Endocr Relat Cancer 19, 57-68 (13 February 2012)

Multiple roles for the p85{alpha} isoform in the regulation and function of PI3K signalling and receptor trafficking
P. Mellor, L. A. Furber, J. N. K. Nyarko, and D. H. Anderson
Biochem. J. 441, 23-37 (1 January 2012)

Hydrogen Sulfide and L-Cysteine Increase Phosphatidylinositol 3,4,5-Trisphosphate (PIP3) and Glucose Utilization by Inhibiting Phosphatase and Tensin Homolog (PTEN) Protein and Activating Phosphoinositide 3-Kinase (PI3K)/Serine/Threonine Protein Kinase (AKT)/Protein Kinase C{zeta}/{lambda} (PKC{zeta}/{lambda}) in 3T3l1 Adipocytes
P. Manna, and S. K. Jain
J Biol Chem 286, 39848-39859 (18 November 2011)

Structural Basis for Activation and Inhibition of Class I Phosphoinositide 3-Kinases
O. Vadas, J. E. Burke, X. Zhang, A. Berndt, and R. L. Williams
Sci Signal 4, re2-re2 (18 October 2011)

Phosphoinositide 3-Kinase Signaling in Retinal Rod Photoreceptors
I. Ivanovic, D. T. Allen, R. Dighe, Y. Z. Le, R. E. Anderson, and R. V. S. Rajala
IOVS 52, 6355-6362 (11 August 2011)

p85{alpha} Regulates Osteoblast Differentiation by Cross-talking with the MAPK Pathway
X. Wu, S. Chen, S. A. Orlando, J. Yuan, E. T. Kim, V. Munugalavadla, R. S. Mali, R. Kapur, and F.-C. Yang
J Biol Chem 286, 13512-13521 (15 April 2011)

The Phosphoinositide 3-Kinase Regulatory Subunit p85{alpha} Can Exert Tumor Suppressor Properties through Negative Regulation of Growth Factor Signaling
C. M. Taniguchi, J. Winnay, T. Kondo, R. T. Bronson, A. R. Guimaraes, J. O. Aleman, J. Luo, G. Stephanopoulos, R. Weissleder, L. C. Cantley et al.
Cancer Res. 70, 5305-5315 (1 July 2010)

Inositol-requiring 1/X-box-binding protein 1 is a regulatory hub that links endoplasmic reticulum homeostasis with innate immunity and metabolism
R. J. Kaufman, and S. Cao
EMBO Mol Med. 2, 189-192 (17 June 2010)

Impact of rs361072 in the Phosphoinositide 3-Kinase p110{beta} Gene on Whole-Body Glucose Metabolism and Subunit Protein Expression in Skeletal Muscle
R. Ribel-Madsen, P. Poulsen, J. Holmkvist, B. Mortensen, N. Grarup, M. Friedrichsen, T. Jorgensen, T. Lauritzen, J. F.P. Wojtaszewski, O. Pedersen et al.
Diabetes 59, 1108-1112 (1 April 2010)

Direct positive regulation of PTEN by the p85 subunit of phosphatidylinositol 3-kinase
R. B. Chagpar, P. H. Links, M. C. Pastor, L. A. Furber, A. D. Hawrysh, M. D. Chamberlain, and D. H. Anderson
Proc. Natl. Acad. Sci. USA 107, 5471-5476 (23 March 2010)

The PI3K Pathway As Drug Target in Human Cancer
K. D. Courtney, R. B. Corcoran, and J. A. Engelman
JCO 28, 1075-1083 (20 February 2010)

p85 Associates with Unphosphorylated PTEN and the PTEN-Associated Complex
R. Rabinovsky, P. Pochanard, C. McNear, S. M. Brachmann, J. S. Duke-Cohan, L. A. Garraway, and W. R. Sellers
Mol. Cell. Biol. 29, 5377-5388 (1 October 2009)

Ligand-induced EpoR internalization is mediated by JAK2 and p85 and is impaired by mutations responsible for primary familial and congenital polycythemia
R. Sulahian, O. Cleaver, and L. J.-s. Huang
Blood 113, 5287-5297 (21 May 2009)

Regulation of Epithelial-Mesenchymal Transition in Palatal Fusion
W. Yu, L.-B. Ruest, and K. K. H. Svoboda
Exp Biol Med (Maywood) 234, 483-491 (1 May 2009)

Role of the liver in glucose homeostasis in PI 3-kinase p85{alpha}-deficient mice
K. Aoki, J. Matsui, N. Kubota, H. Nakajima, K. Iwamoto, I. Takamoto, Y. Tsuji, A. Ohno, S. Mori, K. Tokuyama et al.
Am. J. Physiol. Endocrinol. Metab. 296, E842-E853 (1 April 2009)

Insulin, the Insulin-Like Growth Factor Axis, and Mortality in Patients With Nonmetastatic Colorectal Cancer
B. M. Wolpin, J. A. Meyerhardt, A. T. Chan, K. Ng, J. A. Chan, K. Wu, M. N. Pollak, E. L. Giovannucci, and C. S. Fuchs
JCO 27, 176-185 (10 January 2009)

Insulin immuno-neutralization in chicken: effects on insulin signaling and gene expression in liver and muscle
J. Dupont, S. Tesseraud, M. Derouet, A. Collin, N. Rideau, S. Crochet, E. Godet, E. Cailleau-Audouin, S. Metayer-Coustard, M. J Duclos et al.
J Endocrinol 197, 531-542 (1 June 2008)

Association between Phosphatidylinositol 3-Kinase Regulatory Subunit p85{alpha} Met326Ile Genetic Polymorphism and Colon Cancer Risk
L. Li, S. J. Plummer, C. L. Thompson, T. C. Tucker, and G. Casey
Clin. Cancer Res. 14, 633-637 (1 February 2008)

Phosphoinositide 3-kinases as a common platform for multi-hormone signaling
E. Hirsch, C. Costa, and E. Ciraolo
J Endocrinol 194, 243-256 (1 August 2007)

Mitochondrial Reactive Oxygen Species Signal Hepatocyte Steatosis by Regulating the Phosphatidylinositol 3-Kinase Cell Survival Pathway
R. Kohli, X. Pan, P. Malladi, M. S. Wainwright, and P. F. Whitington
J Biol Chem 282, 21327-21336 (20 July 2007)

Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers
B. Geering, P. R. Cutillas, G. Nock, S. I. Gharbi, and B. Vanhaesebroeck
Proc. Natl. Acad. Sci. USA 104, 7809-7814 (8 May 2007)

The p85{alpha} Regulatory Subunit of Phosphoinositide 3-Kinase Potentiates c-Jun N-Terminal Kinase-Mediated Insulin Resistance
C. M. Taniguchi, J. O. Aleman, K. Ueki, J. Luo, T. Asano, H. Kaneto, G. Stephanopoulos, L. C. Cantley, and C. R. Kahn
Mol. Cell. Biol. 27, 2830-2840 (15 April 2007)

Regulation of class IA PI3Ks: is there a role for monomeric PI3K subunits?
B. Geering, P. R. Cutillas, and B. Vanhaesebroeck
Biochm. Soc. Trans. 35, 199-203 (1 April 2007)

PTEN Regulation, a Novel Function for the p85 Subunit of Phosphoinositide 3-Kinase
D. F. Barber, M. Alvarado-Kristensson, A. Gonzalez-Garcia, R. Pulido, and A. C. Carrera
Sci Signal 2006, pe49-pe49 (21 November 2006)

Signalling through Class I PI3Ks in mammalian cells
P. T. Hawkins, K. E. Anderson, K. Davidson, and L. R. Stephens
Biochm. Soc. Trans. 34, 647-662 (1 October 2006)

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882