Positive and Negative Regulation of Phosphoinositide 3-Kinase-Dependent Signaling Pathways by Three Different Gene Products of the p85α Regulatory Subunit
Open accessAbstract
Phosphoinositide (PI) 3-kinase is a key mediator of insulin-dependent metabolic actions, including stimulation of glucose transport and glycogen synthesis. The gene for the p85alpha regulatory subunit yields three splicing variants, p85alpha, AS53/p55alpha, and p50alpha. All three have (i) a C-terminal structure consisting of two Src homology 2 domains flanking the p110 catalytic subunit-binding domain and (ii) a unique N-terminal region of 304, 34, and 6 amino acids, respectively. To determine if these regulatory subunits differ in their effects on enzyme activity and signal transduction from insulin receptor substrate (IRS) proteins under physiological conditions, we expressed each regulatory subunit in fully differentiated L6 myotubes using adenovirus-mediated gene transfer with or without coexpression of the p110alpha catalytic subunit. PI 3-kinase activity associated with p50alpha was greater than that associated with p85alpha or AS53. Increasing the level of p85alpha or AS53, but not p50alpha, inhibited both phosphotyrosine-associated and p110-associated PI 3-kinase activities. Expression of a p85alpha mutant lacking the p110-binding site (Deltap85) also inhibited phosphotyrosine-associated PI 3-kinase activity but not p110-associated activity. Insulin stimulation of two kinases downstream from PI-3 kinase, Akt and p70 S6 kinase (p70(S6K)), was decreased in cells expressing p85alpha or AS53 but not in cells expressing p50alpha. Similar inhibition of PI 3-kinase, Akt, and p70(S6K) was observed, even when p110alpha was coexpressed with p85alpha or AS53. Expression of p110alpha alone dramatically increased glucose transport but decreased glycogen synthase activity. This effect was reduced when p110alpha was coexpressed with any of the three regulatory subunits. Thus, the three different isoforms of regulatory subunit can relay the signal from IRS proteins to the p110 catalytic subunit with different efficiencies. They also negatively modulate the PI 3-kinase catalytic activity but to different extents, dependent on the unique N-terminal structure of each isoform. These data also suggest the existence of a mechanism by which regulatory subunits modulate the PI 3-kinase-mediated signals, independent of the kinase activity, possibly through subcellular localization of the catalytic subunit or interaction with additional signaling molecules.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Overexpression of p85α reduces insulin signalling in L6 myotubes.
“overexpression of p85α reduces insulin signalling in L6 myotubes [45]”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B
Cross, D. A. E., Alessi, D. R., Cohen, P., Andjelkovich, M., & Hemmings, B. A. (1995) · Nature · doi:10.1038/378785a0 · Cited by 5,244 · see citing works
White, M. F., & Kahn, C. R. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)42297-6 · Cited by 1,723 · see citing works
Self-citationFruman, D. A., Meyers, R., & Cantley, L. C. (1998) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.67.1.481 · Cited by 1,261 · see citing works
Cheatham, B., Vlahos, C. J., Cheatham, L. A., Wang, L., Blenis, J., & Kahn, C. R. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.7.4902-4911.1994 · Cited by 1,067 · see citing works
Self-citationPhosphoinositide 3-kinase: the key switch mechanism in insulin signalling
SHEPHERD, P. R., WITHERS, D. J., & SIDDLE, K. (1998) · Biochemical Journal · doi:10.1042/bj3330471 · Cited by 953 · see citing works
Okada, T., Kawano, Y., Sakakibara, T., Hazeki, O., & Ui, M. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)41901-6 · Cited by 917 · see citing works
Insulin Action, Diabetogenes, and the Cause of Type II Diabetes
Kahn, C. R. (1994) · Diabetes · doi:10.2337/diab.43.8.1066 · Cited by 916 · see citing works
Self-citationProtein–protein interaction in insulin signaling and the molecular mechanisms of insulin resistance
Virkamäki, A., Ueki, K., & Kahn, C. R. (1999) · Journal of Clinical Investigation · doi:10.1172/jci6609 · Cited by 854 · cited 4× · see citing works
“Upon stimulation, the activated insulin receptor tyrosine kinase phosphorylates several intracellular substrates, leading to stimulation of a wide variety of metabolic and mitogenic actions (20, 37).”
BackgroundInfluentialSelf-citationMiyake, S., Makimura, M., Kanegae, Y., Harada, S., Sato, Y., Takamori, K., Tokuda, C., & Saito, I. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.3.1320 · Cited by 788 · see citing works
Otsu, M., Hiles, I., Gout, I. T., Fry, M., Ruiz‐Larrea, F., Panayotou, G., Thompson, A., Dhand, R., Hsuan, J. J., Totty, N. F., et al. (1991) · Cell · doi:10.1016/0092-8674(91)90411-q · Cited by 764 · see citing works
Impaired B Cell Development and Proliferation in Absence of Phosphoinositide 3-Kinase p85α
Fruman, D. A., Snapper, S. B., Yballe, C. M., Davidson, L., Yu, J., Alt, F. W., & Cantley, L. C. (1999) · Science · doi:10.1126/science.283.5400.393 · Cited by 633 · see citing works
The GTPase dynamin binds to and is activated by a subset of SH3 domains
Gout, I. T., Dhand, R., Hiles, I. D., Fry, M., Panayotou, G., Das, P., Truong, O., Totty, N. F., Hsuan, J. J., Booker, G. W., et al. (1993) · Cell · doi:10.1016/s0092-8674(05)80081-9 · Cited by 557 · see citing works
Yu, J., Zhang, Y., McIlroy, J., Rordorf-Nikolic, T., Orr, G. A., & Backer, J. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.3.1379 · Cited by 520 · see citing works
Activation of Phosphatidylinositol-3′ Kinase by Src-Family Kinase SH3 Binding to the p85 Subunit
Pleiman, C. M., Hertz, W., & Cambier, J. C. (1994) · Science · doi:10.1126/science.8128248 · Cited by 440 · see citing works
Hara, K., Yonezawa, K., Sakaue, H., Ando, A., Kotani, K., Kitamura, T., Kitamura, Y., Ueda, H., Stephens, L., & Jackson, T. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.16.7415 · Cited by 433 · see citing works
Terauchi, Y., Tsuji, Y., Satoh, S., Minoura, H., Murakami, K., Okuno, A., Inukai, K., Asano, T., Kaburagi, Y., Ueki, K., et al. (1999) · Nature Genetics · doi:10.1038/6023 · Cited by 399 · see citing works
Self-citationUeki, K., Yamamoto‐Honda, R., Kaburagi, Y., Yamauchi, T., Tobe, K., Burgering, B. M. T., Coffer, P. J., Komuro, I., Akanuma, Y., Yazaki, Y., et al. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.9.5315 · Cited by 356 · see citing works
Self-citationKerouz, N., Hörsch, D., Pons, S., & Kahn, C. R. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119872 · Cited by 301 · see citing works
Self-citationPons, S., Asano, T., Glasheen, E. M., Miralpeix, M., Zhang, Y., Fisher, T. L., Myers, M. G., Sun, X., & White, M. F. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.8.4453 · Cited by 243 · see citing works
Méndez, R., Myers, M. G., White, M. F., & Rhoads, R. E. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.6.2857 · Cited by 218 · see citing works
Hara, K. (1994) · Medical Entomology and Zoology · Cited by 197 · see citing works
Katagiri, H., Asano, T., Ishihara, H., Inukai, K., Shibasaki, Y., Kikuchi, M., Yazaki, Y., & Oka, Y. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.29.16987 · Cited by 194 · see citing works
Rac GTPase interacts specifically with phosphatidylinositol 3-kinase
Bokoch, G., Vlahos, C. J., Wang, Y., Knaus, U. G., & Traynor‐Kaplan, A. (1996) · Biochemical Journal · doi:10.1042/bj3150775 · Cited by 185 · see citing works
Regulation of the p85/p110α Phosphatidylinositol 3′-Kinase
Yu, J., Wjasow, C., & Backer, J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.46.30199 · Cited by 183 · see citing works
Anai, M., Funaki, M., Ogihara, T., Terasaki, J., Inukai, K., Katagiri, H., Fukushima, Y., Yazaki, Y., Kikuchi, M., Oka, Y., et al. (1998) · Diabetes · doi:10.2337/diab.47.1.13 · Cited by 180 · see citing works
Frevert, E. U., & Kahn, B. B. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.1.190 · Cited by 178 · see citing works
Dynamics of Insulin Signaling in 3T3-L1 Adipocytes
Inoue, G., Cheatham, B., Emkey, R., & Kahn, C. R. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.19.11548 · Cited by 168 · see citing works
Self-citationClark, S. F., Martin, S., Carozzi, A., Hill, M. M. C., & James, D. E. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.140.5.1211 · Cited by 168 · see citing works
Inukai, K., Funaki, M., Ogihara, T., Katagiri, H., Kanda, A., Anai, M., Fukushima, Y., Hosaka, T., Suzuki, M., Shin, B., et al. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.12.7873 · Cited by 166 · see citing works
Antonetti, D. A., Algenstaedt, P., & Kahn, C. R. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.5.2195 · Cited by 146 · see citing works
Self-citationSakaue, H., Ogawa, W., Takata, M., Kuroda, S., Kotani, K., Matsumoto, M., Sakaue, M., Nishio, S., Ueno, H., & Kasuga, M. (1997) · Molecular Endocrinology · doi:10.1210/mend.11.10.9986 · Cited by 125 · see citing works
Inukai, K., Anai, M., van Breda, E., Hosaka, T., Katagiri, H., Funaki, M., Fukushima, Y., Ogihara, T., Yazaki, Y., Kikuchi, M., et al. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.10.5317 · Cited by 124 · see citing works
Sharma, P. M., Egawa, K., Huang, Y., Martin, J. W., Huvar, I., Boss, G. R., & Olefsky, J. M. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.29.18528 · Cited by 118 · see citing works
Structural Organization and Alternative Splicing of the Murine Phosphoinositide 3-Kinase p85α Gene
Fruman, D. A., Cantley, L. C., & Carpenter, C. L. (1996) · Genomics · doi:10.1006/geno.1996.0527 · Cited by 115 · see citing works
Upstream Mechanisms of Glycogen Synthase Activation by Insulin and Insulin-like Growth Factor-I
Yamamoto‐Honda, R., Tobe, K., Kaburagi, Y., Ueki, K., Asai, S., Yachi, M., Shirouzu, M., Yodoi, J., Akanuma, Y., Yokoyama, S., et al. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.6.2729 · Cited by 109 · see citing works
Self-citationEgawa, K., Sharma, P. M., Nakashima, N., Huang, Y., Huver, E., Boss, G. R., & Olefsky, J. M. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.20.14306 · Cited by 90 · see citing works
MARCHAND‐BRUSTEL, Y. L., Gautier, N., Cormont, M., & OBBERGHEN, E. V. (1995) · Endocrinology · doi:10.1210/endo.136.8.7628394 · Cited by 84 · see citing works
Sakaue, H., Hara, K., Noguchi, T., Matozaki, T., Kotani, K., Ogawa, W., Yonezawa, K., Kasuga, M., & Waterfield, M. D. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.19.11304 · Cited by 72 · see citing works
Shepherd, P. R., NAVÉ, B. T., Rincón, J., Nolte, L. A., Bevan, A. P., Siddle, K., Zierath, J. R., & Wallberg‐Henriksson, H. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.30.19000 · Cited by 63 · see citing works
Intermolecular Interactions of the p85α Regulatory Subunit of Phosphatidylinositol 3-Kinase
Harpur, A. G., Layton, M. J., Das, P., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.18.12323 · Cited by 57 · see citing works
Hunter, S., Koch, B. L., & Anderson, S. M. (1997) · Molecular Endocrinology · doi:10.1210/mend.11.9.9980 · Cited by 47 · see citing works
Phosphoinositide 3-kinase knockout mice: role of p85α in B cell development and proliferation
Fruman, D. A., Snapper, S. B., Yballe, C. M., et al. (1999) · Biochemical Society Transactions · doi:10.1042/bst0270624 · Cited by 38 · see citing works
PI 3-Kinase Activation Is Required for Insulin Stimulation of Glucose Transport into L6 Myotubes
Berger, J., Hayes, D. N., Szalkowski, D., et al. (1994) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1994.2703 · Cited by 36 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Critical nodes in signalling pathways: insights into insulin action
Taniguchi, C. M., Emanuelli, B., & Kahn, C. R. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1837 · Cited by 2,760 · see citing works
Self-citationAwazawa, M., Ueki, K., Inabe, K., Yamauchi, T., Kubota, N., Kaneko, K., Kobayashi, M., Iwane, A., Sasako, T., Okazaki, Y., et al. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.02.010 · Cited by 277 · see citing works
Self-citationRuzzin, J., Wagman, A. S., & Jensen, J. (2005) · Diabetologia · doi:10.1007/s00125-005-1886-0 · Cited by 243 · see citing works
Bandyopadhyay, G. K., Yu, J. G., Ofrecio, J., & Olefsky, J. M. (2005) · Diabetes · doi:10.2337/diabetes.54.8.2351 · Cited by 210 · see citing works
Barbour, L. A., Shao, J., Qiao, L., Leitner, W., Anderson, M., Friedman, J. E., & Draznin, B. (2004) · Endocrinology · doi:10.1210/en.2003-1297 · Cited by 208 · see citing works
Mauvais-Jarvis, F., Ueki, K., Fruman, D. A., Hirshman, M. F., Sakamoto, K., Goodyear, L. J., Iannacone, M., Accili, D., Cantley, L. C., & Kahn, C. R. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0213305 · Cited by 207 · see citing works
Self-citationFriedman, J. E., Kirwan, J. P., Jing, M., Presley, L., & Catalano, P. M. (2008) · Diabetes · doi:10.2337/db07-1356 · Cited by 98 · see citing works
Cornier, M.-A., Bessesen, D. H., Gurevich, I., Leitner, J. W., & Draznin, B. (2006) · Diabetologia · doi:10.1007/s00125-006-0148-0 · Cited by 35 · see citing works
- Authors
- Ueki, K., Algenstaedt, P., Mauvais-Jarvis, F., & Kahn, C. R.
- Affiliations
- Joslin Diabetes Center (US)
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2000-11-01
- Volume
- 20
- Issue
- 21
- Pages
- 8035-8046
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC86414
- OpenAlex
- W2141067543
- Cited by
- 148
- References
- 43
- Citations by year
- 2025: 2 · 2024: 3 · 2023: 1 · 2022: 3 · 2021: 5 · 2020: 4 · 2019: 2 · 2018: 5 · 2017: 2 · 2016: 4 · 2015: 5 · 2014: 2 · 2013: 9 · 2012: 3
- FWCI
- 3.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK055545, DK 33201, R01DK033201, DK55545)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- phosphatidylinositol 3-kinase, p85alpha regulatory subunit, alternative splicing, insulin receptor substrate, insulin signaling, Akt, p70 S6 kinase, glucose transport, glycogen synthase, negative regulation of signaling, L6 myotubes, adenoviral gene transfer
- MeSH terms
- Adenoviridae, Amino Acids, Animals, Binding Sites, Biological Transport, Cell Line, Deoxyglucose, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Glucose, Insulin, Models, Biological, Precipitin Tests, Receptor, Insulin, Time Factors, Blotting, Western, Signal Transduction, Gene Expression Regulation, Enzymologic, Alternative Splicing, Gene Transfer Techniques, DNA, Complementary, src Homology Domains, Phosphotyrosine, Phosphatidylinositol 3-Kinases, Ribosomal Protein S6 Kinases, Protein Isoforms, Catalytic Domain, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
