PI3K Activation, Inhibition, & Medical Implications

From Proteopedia

Activation of Class IA PI3K

Inactive PI3Ks are rapidly activated in the presence of extracellular stimuli. Such stimuli, as discussed previously, include growth factor receptors with intrinsic protein tyrosine kinase activity, which display pYXXM motifs for p85 docking, as well as receptor substrates which are phosphorylated and interact with PI3K regulatory subunits like nSH2. PI3K can be additionally activated in cooperative processes like translocation to the plasma membrane where lipid substrates are available and by binding GTP loaded Ras to the catalytic subunit. ^[1]^[2]

PI3K Inhibition

The Phosphorylated Lipid Products in Downstream Signaling

Ligand receptor interactions trigger a rapid rise of cellular PIP3. Numerous molecular targets are activated upon interaction with PIP3. One such target is the Ser/Thr kinase Akt, which requires the action of phosphoinositide dependent kinases, another step for potential fine tuning. Akt subsequently inactivates glycogen-synthase-kinase 3 and the pro-apoptotic factor BAD. ^[8]. PIP3 also activates Btk, an essential protein for normal B lymphocyte development and function ^[9] along with dozens of other targets including centaurin, profiling, cytohesin, etc. which control^[2]

Medical Implications

PI3K In Medicine

As mentioned previously, the class I PI3Ks play a critical role in the transmission of proliferation and survival signals in a wide variety of cell types. Due to PI3Ks intricate activation system by numerous targets, mutations at key positions in PI3K have been identified to cause various types of cancer. These positions are known as “Hotspots.” These hotspots are located in both the p85 subunit and p110 subunit. For example, a mutation in the known to cause glioblastoma is G376R. a crucial residue in one of the stabilizing C2 domain loops. ^[6] Somatic mutations in the gene encoding the p110 catalytic subunit can be grouped into the four classes of the catalytic subunit in which they occur, the ABD, C2, helical and catalytic domains, all of which likely increase PI3K activity by different mechanisms.^[10] For example, two well known cancer causing mutations map to , at residues . These residues lie at the interface of the ABD and Kinase domains and are believed to alter regulation of the catalytic subunit. Other mutations, such as those in the C2 domain, up regulate PI3K, by increasing the affinity for substrate containing membranes, resulting in elevated levels of PIP3. ^[10] Aberrations in PIP3 levels, either through activation of PI3Ks or through inactivation of lipid phosphatase PTEN, occur frequently in numerous forms of cancer. Recent data suggest that at least 50% of human breast cancers involve mutations in either PI3K or PTEN. ^[10]

The dramatic number of mutations in PI3K associated with Cancer has resulted in PIK3CA, the gene that encodes the catalytic p100( domain of PIK3, being identified as a human oncogene. More than 1500 PIK3CA mutations, nearly all of which increase lipid kinase activity, have been identified in different tumor types, the most common being breast and uterine cancers. ^[6] Further, the lipid products of PI3K interact with other well known oncogenes like akt2, akt3, PDGFR, PTEN, among many others. ^[7]

In addition to cancer, faulty PI3K function has been associated with disorders like heart failure ^[11], diabetes, ^[12], and inflammation.^[13]

Current Pharmaceutical Approaches

Broad spectrum PI3K inhibitors have exhibited impressive results, revealing increased apoptosis and decreased proliferation in tumor models.^[10] The primary focus now amongst medicinal researchers is to identify PI3K inhibitors with increased selectivity (particularly for p110) and bioavailability. Use of inhibitors such as wortmannin have identified slightly different binding mechanisms between PI3K isoforms, creating the potential for highly selective compounds to neutralize secific PI3K isotypes while leaving other forms of the ubiquitous protein unaltered.PI3K stands as one of the most promising targets for pharmaceutical intervention of cancer.^[14]

Additional Resources

See Phosphoinositide 3-Kinases for the main page or The Structure of PI3K for information on PI3K's structure and function.
See Cancer for additional information.
See Diabetes for additional information.

References

↑ Gout I, Dhand R, Hiles ID, Fry MJ, Panayotou G, Das P, Truong O, Totty NF, Hsuan J, Booker GW, et al.. The GTPase dynamin binds to and is activated by a subset of SH3 domains. Cell. 1993 Oct 8;75(1):25-36. PMID:8402898
↑ ^2.0 ^2.1 Wymann MP, Pirola L. Structure and function of phosphoinositide 3-kinases. Biochim Biophys Acta. 1998 Dec 8;1436(1-2):127-50. PMID:9838078
↑ Wymann MP, Pirola L. Structure and function of phosphoinositide 3-kinases. Biochim Biophys Acta. 1998 Dec 8;1436(1-2):127-50. PMID:9838078
↑ ^4.0 ^4.1 Stein RC. Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment. Endocr Relat Cancer. 2001 Sep;8(3):237-48. PMID:11566615
↑ Sutton PR. Are most fluoridation promoters neurotics? Med Hypotheses. 1992 Nov;39(3):199-200. PMID:1474947
↑ ^6.0 ^6.1 ^6.2 Mandelker D, Gabelli SB, Schmidt-Kittler O, Zhu J, Cheong I, Huang CH, Kinzler KW, Vogelstein B, Amzel LM. A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane. Proc Natl Acad Sci U S A. 2009 Oct 6;106(40):16996-7001. Epub 2009 Sep 23. PMID:19805105
↑ ^7.0 ^7.1 ^7.2 Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP, Williams RL. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell. 2000 Oct;6(4):909-19. PMID:11090628
↑ Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997 Oct 17;91(2):231-41. PMID:9346240
↑ de Weers M, Mensink RG, Kraakman ME, Schuurman RK, Hendriks RW. Mutation analysis of the Bruton's tyrosine kinase gene in X-linked agammaglobulinemia: identification of a mutation which affects the same codon as is altered in immunodeficient xid mice. Hum Mol Genet. 1994 Jan;3(1):161-6. PMID:8162018
↑ ^10.0 ^10.1 ^10.2 ^10.3 Miled N, Yan Y, Hon WC, Perisic O, Zvelebil M, Inbar Y, Schneidman-Duhovny D, Wolfson HJ, Backer JM, Williams RL. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science. 2007 Jul 13;317(5835):239-42. PMID:17626883 doi:317/5835/239
↑ Lin RC, Weeks KL, Gao XM, Williams RB, Bernardo BC, Kiriazis H, Matthews VB, Woodcock EA, Bouwman RD, Mollica JP, Speirs HJ, Dawes IW, Daly RJ, Shioi T, Izumo S, Febbraio MA, Du XJ, McMullen JR. PI3K(p110 alpha) protects against myocardial infarction-induced heart failure: identification of PI3K-regulated miRNA and mRNA. Arterioscler Thromb Vasc Biol. 2010 Apr;30(4):724-32. PMID:20237330 doi:10.1161/ATVBAHA.109.201988
↑ Carracedo A, Pandolfi PP. The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene. 2008 Sep 18;27(41):5527-41. PMID:18794886 doi:10.1038/onc.2008.247
↑ Sasaki T, Irie-Sasaki J, Horie Y, Bachmaier K, Fata JE, Li M, Suzuki A, Bouchard D, Ho A, Redston M, Gallinger S, Khokha R, Mak TW, Hawkins PT, Stephens L, Scherer SW, Tsao M, Penninger JM. Colorectal carcinomas in mice lacking the catalytic subunit of PI(3)Kgamma. Nature. 2000 Aug 24;406(6798):897-902. PMID:10972292 doi:10.1038/35022585
↑ Crabbe T. Exploring the potential of PI3K inhibitors for inflammation and cancer. Biochem Soc Trans. 2007 Apr;35(Pt 2):253-6. PMID:17371252 doi:10.1042/BST0350253

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PI3K Activation, Inhibition, & Medical Implications

From Proteopedia

Activation of Class IA PI3K

PI3K Inhibition

Inhibition by Wortmannin, LY294002 & Others: Implications

Wortmannin Binding

LY294002, Quercetin, Myricetin & Staurosporine

The Phosphorylated Lipid Products in Downstream Signaling

Medical Implications

PI3K In Medicine

Current Pharmaceutical Approaches

Additional Resources

References

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