The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index.
Intramolecular and Intermolecular Interactions of Protein Kinase B Define Its Activation In Vivo
Open accessAbstract
Protein kinase B (PKB/Akt) is a pivotal regulator of diverse metabolic, phenotypic, and antiapoptotic cellular controls and has been shown to be a key player in cancer progression. Here, using fluorescent reporters, we shown in cells that, contrary to in vitro analyses, 3-phosphoinositide-dependent protein kinase 1 (PDK1) is complexed to its substrate, PKB. The use of Förster resonance energy transfer detected by both frequency domain and two-photon time domain fluorescence lifetime imaging microscopy has lead to novel in vivo findings. The preactivation complex of PKB and PDK1 is maintained in an inactive state through a PKB intramolecular interaction between its pleckstrin homology (PH) and kinase domains, in a "PH-in" conformer. This domain-domain interaction prevents the PKB activation loop from being phosphorylated by PDK1. The interactive regions for this intramolecular PKB interaction were predicted through molecular modeling and tested through mutagenesis, supporting the derived model. Physiologically, agonist-induced phosphorylation of PKB by PDK1 occurs coincident to plasma membrane recruitment, and we further shown here that this process is associated with a conformational change in PKB at the membrane, producing a "PH-out" conformer and enabling PDK1 access the activation loop. The active, phosphorylated, "PH-out" conformer can dissociate from the membrane and retain this conformation to phosphorylate substrates distal to the membrane. These in vivo studies provide a new model for the mechanism of activation of PKB. This study takes a crucial widely studied regulator (physiology and pathology) and addresses the fundamental question of the dynamic in vivo behaviour of PKB with a detailed molecular mechanism. This has important implications not only in extending our understanding of this oncogenic protein kinase but also in opening up distinct opportunities for therapeutic intervention.
Overview
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
Verification
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.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Electrostatics of nanosystems: Application to microtubules and the ribosome
Baker, N. A., Sept, D., Joseph, S., Holst, M. J., & McCammon, J. A. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.181342398 · Cited by 7,172
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
Sarbassov, D. D., Guertin, D. A., Ali, S. M., & Sabatini, D. M. (2005) · Science · doi:10.1126/science.1106148 · Cited by 6,216
Mechanism of activation of protein kinase B by insulin and IGF-1.
Alessi, D. R., Andjelkovic, M., Caudwell, B., Cron, P., Morrice, N., Cohen, P., & Hemmings, B. A. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb01045.x · Cited by 3,004
Self-citationAlessi, D. R., James, S. R., Downes, C. P., Holmes, A. B., Gaffney, P. R. J., Reese, C. B., & Cohen, P. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00122-9 · Cited by 2,826
Franke, T. F., Yang, S.-I., Chan, T. O., Datta, K., Kazlauskas, A., Morrison, D. K., Kaplan, D. R., & Tsichlis, P. N. (1995) · Cell · doi:10.1016/0092-8674(95)90534-0 · Cited by 2,006
The activation of Akt/PKB signaling pathway and cell survival
Song, G., Ouyang, G., & Bao, S. (2005) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2005.tb00337.x · Cited by 1,888
The protein kinase B/Akt signalling pathway in human malignancy
Nicholson, K. M., & Anderson, N. G. (2002) · Cellular Signalling · doi:10.1016/s0898-6568(01)00271-6 · Cited by 1,639
Role of Translocation in the Activation and Function of Protein Kinase B
Andjelkovic, M., Alessi, D. R., Meier, R., Fernandez, A., Lamb, N. J. C., Frech, M., Cron, P., Cohen, P., Lucocq, J. M., & Hemmings, B. A. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.50.31515 · Cited by 1,051
Self-citationGao, T., Furnari, F., & Newton, A. C. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.03.008 · Cited by 906
Brown, R. A., & Motulsky, H. (1997) · Biometrics · doi:10.2307/2533525 · Cited by 800
Stauffer, T. P., Ahn, S., & Meyer, T. (1998) · Current Biology · doi:10.1016/s0960-9822(98)70135-6 · Cited by 761
Crystal structure of an activated Akt/Protein Kinase B ternary complex with GSK3-peptide and AMP-PNP
Yang, J., Cron, P., Good, V. M., Thompson, V., Hemmings, B. A., & Barford, D. (2002) · Nature Structural Biology · doi:10.1038/nsb870 · Cited by 503
Self-citationMolecular Mechanism for the Regulation of Protein Kinase B/Akt by Hydrophobic Motif Phosphorylation
Yang, J., Cron, P., Thompson, V., Good, V. M., Hess, D., Hemmings, B. A., & Barford, D. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00550-6 · Cited by 418
Self-citationCurrie, R. A., Walker, K. S., Alex, G. R. A. Y., Deák, M., Casamayor, A., Downes, C. P., Cohen, P., Alessi, D. R., & Lucocq, J. M. (1999) · Biochemical Journal · doi:10.1042/0264-6021:3370575 · Cited by 379
Thomas, C. C., Deak, M., Alessi, D. R., & van Aalten, D. M. F. (2002) · Current Biology · doi:10.1016/s0960-9822(02)00972-7 · Cited by 300
Watton, S. J., & Downward, J. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80192-4 · Cited by 293
Self-citationApplication of the Stretched Exponential Function to Fluorescence Lifetime Imaging
Lee, K. C. B., Siegel, J., Webb, S. E. D., Lévêque-Fort, S., Cole, M. J., Jones, R., Dowling, K., Lever, M. J., & French, P. M. W. (2001) · Biophysical Journal · doi:10.1016/s0006-3495(01)75784-0 · Cited by 279
MILBURN, C. C., DEAK, M., KELLY, S. M., PRICE, N. C., ALESSI, D. R., & van AALTEN, D. M. F. (2003) · Biochemical Journal · doi:10.1042/bj20031229 · Cited by 264
Inhibition of protein kinase B/Akt
Hill, M. M., & Hemmings, B. A. (2002) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(02)00193-6 · Cited by 245
Self-citationAKT/PKB signaling mechanisms in cancer and chemoresistance
Kim, D. (2005) · Frontiers in Bioscience · doi:10.2741/1592 · Cited by 204
Tramier, M., Zahid, M., Mevel, J., Masse, M., & Coppey‐Moisan, M. (2006) · Microscopy Research and Technique · doi:10.1002/jemt.20370 · Cited by 183
In vivo role of the PIF-binding docking site of PDK1 defined by knock-in mutation
Collins, B. J. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg407 · Cited by 180
Crystal Structure of an Inactive Akt2 Kinase Domain
Huang, X., Begley, M., Morgenstern, K. A., Gu, Y., Rose, P., Zhao, H., & Zhu, X. (2003) · Structure · doi:10.1016/s0969-2126(02)00937-1 · Cited by 136
Filippa, N., Sable, C. L., Hemmings, B. A., & OBBERGHEN, E. V. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.15.5712-5721.2000 · Cited by 130
Self-citationPark, J., Hill, M. M. C., Heß, D., Brazil, D. P., Hofsteenge, J., & Hemmings, B. A. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105916200 · Cited by 126
Self-citationAndjelković, M., Maira, S.-M., Cron, P. D., Parker, P. J., & Hemmings, B. A. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.7.5061 · Cited by 111
Self-citationMonitoring conformational changes of proteins in cells by fluorescence lifetime imaging microscopy
Calleja, V., Ameer‐Beg, S., Vojnovic, B., Woscholski, R., Downward, J., & Larijani, B. (2003) · Biochemical Journal · doi:10.1042/bj20030358 · Cited by 106
Self-citationChen, D., Fucini, R. V., Olson, A. L., Hemmings, B. A., & Pessin, J. E. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.7.4684 · Cited by 104
Self-citationLining the pockets of kinases and phosphatases
Gold, M. G., Barford, D., & Komander, D. (2006) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2006.10.006 · Cited by 85
In vivo role of the phosphate groove of PDK1 defined by knockin mutation
Collins, B., Deák, M., Murray-Tait, V., Storey, K. G., & Alessi, D. R. (2005) · Journal of Cell Science · doi:10.1242/jcs.02617 · Cited by 58
Larijani, B., Allen-Baume, V., Morgan, C. P., Li, M., & Cockcroft, S. (2003) · Current Biology · doi:10.1016/s0960-9822(02)01395-7 · Cited by 37
Self-citationMLPP: A Program for the Calculation of Molecular Lipophilicity Potential in Proteins
Laguerre, M., Saux, M., Dubost, J. P., & Carpy, A. (1997) · Pharmacy and Pharmacology Communications · doi:10.1111/j.2042-7158.1997.tb00257.x · Cited by 29
Self-citation
Cited by
AKT/PKB Signaling: Navigating the Network
Manning, B. D., & Toker, A. (2017) · Cell · doi:10.1016/j.cell.2017.04.001 · Cited by 3,772
The nuts and bolts of AGC protein kinases
Pearce, L. R., Komander, D., & Alessi, D. R. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2822 · Cited by 1,294
Akt signalling in health and disease
Hers, I., Vincent, E. E., & Tavaré, J. M. (2011) · Cellular Signalling · doi:10.1016/j.cellsig.2011.05.004 · Cited by 1,239
García-Martínez, J. M., & Alessi, D. R. (2008) · Biochemical Journal · doi:10.1042/bj20081668 · Cited by 907
PI3K/Akt: getting it right matters
Franke, T. F. (2008) · Oncogene · doi:10.1038/onc.2008.313 · Cited by 695
Metadata
- Authors
- Calleja, V., Alcor, D., Laguerre, M., Park, J., Vojnovic, B., Hemmings, B. A., Downward, J., Parker, P. J., & Larijani, B.
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2007-04-03
- Volume
- 5
- Issue
- 4
- Pages
- e95
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- OpenAlex
- W2027731629
- Cited by
- 301
- References
- 32
- FWCI
- 8.26
- Type
- journal article
- Language
- en
- Open access
- gold
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
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
