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Sci. Signal., 18 October 2011
Vol. 4, Issue 195, p. re2
[DOI: 10.1126/scisignal.2002165]


Structural Basis for Activation and Inhibition of Class I Phosphoinositide 3-Kinases

Oscar Vadas*, John E. Burke, Xuxiao Zhang{dagger}, Alex Berndt, and Roger L. Williams*

Medical Research Council, Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
{dagger} Present address: School of Biological Science, Nanyang Technological University, 138673 Singapore.

Gloss: Phosphoinositide 3-kinases (PI3Ks) phosphorylate a hydroxyl group on phosphoinositide lipids. The 3-phosphorylated inositol lipids act as membrane-resident second messengers, recruiting downstream signaling components that control cell growth, proliferation, differentiation, survival, and motility. The best studied of the PI3Ks, the class I enzymes, are heterodimers with a catalytic and a regulatory subunit and have been implicated in many human diseases. Class I PI3Ks can be stimulated downstream of receptor tyrosine kinases and heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors as well as small G proteins of the Ras superfamily. Both the catalytic and regulatory subunits have a multidomain organization. Crystal structures, biochemical analysis, and oncogenic mutations in PI3Ks have shown that interdomain interactions are not static but undergo regulated conformational cycles, resulting in enzyme activation or inhibition. This Review, which contains 7 figures and 104 references, highlights the molecular details of how their regulatory partners selectively inhibit and activate PI3K isoforms.

* To whom correspondence should be addressed. E-mail: ovadas{at} (O.V.); rlw{at} (R.L.W.)

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

Classes of phosphoinositide 3-kinases at a glance.
S. Jean and A. A. Kiger (2014)
J. Cell Sci. 127, 923-928
   Abstract »    Full Text »    PDF »
DW09849, a Selective Phosphatidylinositol 3-Kinase (PI3K) Inhibitor, Prevents PI3K Signaling and Preferentially Inhibits Proliferation of Cells Containing the Oncogenic Mutation p110{alpha} (H1047R).
J.-l. Liu, G.-r. Gao, X. Zhang, S.-f. Cao, C.-l. Guo, X. Wang, L.-j. Tong, J. Ding, W.-h. Duan, and L.-h. Meng (2014)
J. Pharmacol. Exp. Ther. 348, 432-441
   Abstract »    Full Text »    PDF »
The Structural Basis of PI3K Cancer Mutations: From Mechanism to Therapy.
S. Liu, S. Knapp, and A. A. Ahmed (2014)
Cancer Res. 74, 641-646
   Abstract »    Full Text »    PDF »
Targeting Small Cell Lung Cancer Harboring PIK3CA Mutation with a Selective Oral PI3K Inhibitor PF-4989216.
M. Walls, S. M. Baxi, P. P. Mehta, K. K.- C. Liu, J. Zhu, H. Estrella, C. Li, M. Zientek, Q. Zong, T. Smeal, et al. (2014)
Clin. Cancer Res. 20, 631-643
   Abstract »    Full Text »    PDF »
Insulin Receptor Signaling in Normal and Insulin-Resistant States.
J. Boucher, A. Kleinridders, and C. R. Kahn (2014)
Cold Spring Harb Perspect Biol 6, a009191
   Abstract »    Full Text »    PDF »
Molecular determinants of PI3K{gamma}-mediated activation downstream of G-protein-coupled receptors (GPCRs).
O. Vadas, H. A. Dbouk, A. Shymanets, O. Perisic, J. E. Burke, W. F. Abi Saab, B. D. Khalil, C. Harteneck, A. R. Bresnick, B. Nurnberg, et al. (2013)
PNAS 110, 18862-18867
   Abstract »    Full Text »    PDF »
Phosphoinositide 3-Kinase {delta} Gene Mutation Predisposes to Respiratory Infection and Airway Damage.
I. Angulo, O. Vadas, F. Garcon, E. Banham-Hall, V. Plagnol, T. R. Leahy, H. Baxendale, T. Coulter, J. Curtis, C. Wu, et al. (2013)
Science 342, 866-871
   Abstract »    Full Text »    PDF »
p87 and p101 Subunits Are Distinct Regulators Determining Class IB Phosphoinositide 3-Kinase (PI3K) Specificity.
A. Shymanets, Prajwal, K. Bucher, S. Beer-Hammer, C. Harteneck, and B. Nurnberg (2013)
J. Biol. Chem. 288, 31059-31068
   Abstract »    Full Text »    PDF »
Differential Roles of CXCL2 and CXCL3 and Their Receptors in Regulating Normal and Asthmatic Airway Smooth Muscle Cell Migration.
L. A. Al-Alwan, Y. Chang, A. Mogas, A. J. Halayko, C. J. Baglole, J. G. Martin, S. Rousseau, D. H. Eidelman, and Q. Hamid (2013)
J. Immunol. 191, 2731-2741
   Abstract »    Full Text »    PDF »
Cyclooxygenase-2 Deficiency in Macrophages Leads to Defective p110{gamma} PI3K Signaling and Impairs Cell Adhesion and Migration.
M. D. Diaz-Munoz, I. C. Osma-Garcia, M. A. Iniguez, and M. Fresno (2013)
J. Immunol. 191, 395-406
   Abstract »    Full Text »    PDF »
Selective Inactivation of PTEN in Smooth Muscle Cells Synergizes With Hypoxia to Induce Severe Pulmonary Hypertension.
H. Horita, S. B. Furgeson, A. Ostriker, K. A. Olszewski, T. Sullivan, L. R. Villegas, M. Levine, J. E. Parr, C. D. Cool, R. A. Nemenoff, et al. (2013)
JAHA 2, e000188
   Abstract »    Full Text »    PDF »
The Expanding Roles of G{beta}{gamma} Subunits in G Protein-Coupled Receptor Signaling and Drug Action.
S. M. Khan, R. Sleno, S. Gora, P. Zylbergold, J.-P. Laverdure, J.-C. Labbe, G. J. Miller, and T. E. Hebert (2013)
Pharmacol. Rev. 65, 545-577
   Abstract »    Full Text »    PDF »
Phosphodiesterase-3 inhibition augments the myocardial infarct size-limiting effects of exenatide in mice with type 2 diabetes.
Y. Ye, J. Qian, A. C. Castillo, S. Ling, H. Ye, J. R. Perez-Polo, M. Bajaj, and Y. Birnbaum (2013)
Am J Physiol Heart Circ Physiol 304, H131-H141
   Abstract »    Full Text »    PDF »
Evolution of the eukaryotic protein kinases as dynamic molecular switches.
S. S. Taylor, M. M. Keshwani, J. M. Steichen, and A. P. Kornev (2012)
Phil Trans R Soc B 367, 2517-2528
   Abstract »    Full Text »    PDF »
Oncogenic mutations mimic and enhance dynamic events in the natural activation of phosphoinositide 3-kinase p110{alpha} (PIK3CA).
J. E. Burke, O. Perisic, G. R. Masson, O. Vadas, and R. L. Williams (2012)
PNAS 109, 15259-15264
   Abstract »    Full Text »    PDF »

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