Phosphoinositide 3-Kinases

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PI3K p110α Subunit, 3hhm
PI3K p110α Subunit, 3hhm
Theoretical Model of PI3K Gamma Catalytic Subunit w/ Adaptor Subunit Components, Compliments of M. Zvelebil, M.D. Waterfield (LICR, London) & Roger Williams (MRC, Cambridge)
Ligands:
Gene: PIK3CA (Homo sapiens), PI3KR1 (Homo sapiens)
Activity: Phosphatidylinositol-4,5-bisphosphate 3-kinase, with EC number 2.7.1.153
Related: 3hiz
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml



Human PI3Kγ catalytic subunit complex with inhibitor and sulfate, 3apc
Ligands: ,
Gene: PIK3CG (Homo sapiens)
Activity: Phosphatidylinositol-4,5-bisphosphate 3-kinase, with EC number 2.7.1.153
Related: 3apd, 3apf


Resources: FirstGlance, OCA, PDBsum, RCSB
Coordinates: save as pdb, mmCIF, xml









Phosphoinositide 3-Kinases (PI3K) are a family of ubiquitously distributed lipid kinases, that play a critical role in the regulation of numerous cellular processes including cellular growth and morphology, programmed cell death, cell motility and adhesion, mitogenesis and glucose uptake. [1] PI3K generates important second messengers by catalyzing the transfer of the γ-phosphate group of ATP to the D3 position of phosphoinositides. [2] The PI3K preferred substrate is Phosphatidylinositol-4,5-bisphosphate (PIP2), which is converted into phosphatidylinositol-3,4,5-triphosphate (PIP3) upon phosphorylation at the cell membrane. The importance of PI3K is evident in knockout mice studies in which those mice with disruptions of critical PI3K components have significant deficiencies in immune and inflammatory response [3] sometimes resulting in embryonic death.[4] Aberrations in PIP3 levels, either through activation of PI3ks or through inactivation of lipid phosphatase PTEN, occur frequently in numerous forms of cancer, making PI3K an exciting new target to treat cancer among other human diseases.[5] For additional details see

Contents

The Classes of PI3Ks

Signal Transduction Pathway. PI3K Highlighted in Red. Click to Expand
Signal Transduction Pathway. PI3K Highlighted in Red. Click to Expand
PI3Ks can be grouped into three distinct classes, Class I-III. Class I PI3Ks, the most well understood and thoroughly explored PI3K class, are composed of a 110kDa and a 50-100 kDa . Activation of Class I PI3Ks is controlled by extracellular signaling via receptors with intrinsic tyrosine kinase activity, G protein-linked receptors, or receptors coupled to SRC like protein tyrosine kinases. [6] Class II PI3Ks are relatively poorly understood but are 170-210 kDa and have in vitro substrate specificity toward PtdIns 4-P. Class III PI3Ks depend on Vps15p protein Ser/Thr kinases, which recruits the phosphatidylinositol kinase to late Golgi Compartments. [2]

Class I Subclasses

PI3Ks are activated by extracellular agonists via the translocation of PI3Ks to the plasma membrane for easy access to lipid substrates. Depending on the adaptor proteins involved in the process, Class I PI3Ks are segregated into two subgroups. Those that associate with p85 will be directed to phosphorylated tyrosine motifs (Class IA), Phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3Kγ) catalyzes the conversion of 1-phosphatidyl-1D-myo-inositol-4, 5-bisphosphate and ATP to 1-phosphatidyl-1D-myo-inositol-4, 5-trisphosphate. PI3Kγ interacts with trimeric G proteins and the p101 protein (Class IB) [2]

Structure of PI3K

For Full Article, See: The Structure of PI3K

Class I PI3Ks, which are tightly regulated by tyrosine kinases, are composed of an 85kDa regulatory/adapter subunit (p85) and a 110kDa catalytic subunit (p110). [7]

PI3K Activation, Inhibition, and Medical Implications

For Full Article, See: PI3K Activation, Inhibition, & Medical Implications

A number of inhibitors for PI3K have been developed to understand how PI3K is activated and functions. These analysis have massive medical implications for the treatment of Cancer and Diabetes.

3D Structures of PI3K

Updated on 20-August-2014

Class I p85α

2iug, 2iuh, 2iui – Crystal Structure of PI3K nSH2 Domain with Peptides
1h9o – Crystal Structure of PI3K SH2 Domain with PDGFR Peptide
2vly - hPI3KI p85α+ABD
1pic - hPI3K p85α subunit SH2 domain + β-platelet-derived growth factor receptor peptide – NMR
1bfi, 1bfj, 2pna, 2pnb - bPI3KI p85α SH2 domain – bovine – NMR
1oo3 - bPI3KI p85α SH2 domain (mutant) – NMR
1oo4 - bPI3KI p85α SH2 domain (mutant) + PDGFR peptide – NMR
1qad - bPI3KI p85α SH2 domain
3i5s, 3i5r, 1pht - hPI3KI p85α SH3 domain
1pks, 1pkt - hPI3KI p85α SH3 domain - NMR
1pnj, 2pni – bPI3K p85α subunit SH3 domain – NMR
1fu5, 1fu6 – NMR structure of nSH2 Domain from PI3K
1pbw, 2xs6 - hPI3K p85α subunit RhoGAP domain

Class I p85β

3mtt, 3o5z – hPI3KI p85β
2kt1 - hPI3KI p85β SH3 domain
3l4q – bPI3KI p85β influenza NS1 protein – bovine

Class I p110α+p85α

3hhm - hTI-PI3K p110α+p85α SH2 domain + wortmannin
3hiz, 4jps - hTI-PI3K p110α (mutant) + p85α
2rd0, 4l1b - hTI-PI3K p110α+p85α
4l23, 4l2y - hTI-PI3K p110α + p85α + inhibitor
2v1y - bTI-PI3K p110α +h-p85α

Class I p110α

2enq - hTI-PI3K p110α C2 domain
3zim, 4a55 - hTI-PI3K p110α + inhibitor

Class I p110β

4bfr - TI-PI3K p110β + inhibitor – mouse
2y3a - hTI-PI3K p110β + p85β + drug

Class I p110γ

3lj3 – hTI-PI3K p110γ + pyrrolopyridine-benzofuran inhibitor
3l54 – hTI-PI3K p110γ + quinoline derivative
3l08 – hTI-PI3K p110γ + GSK2126458
3ibe – hTI-PI3K p110γ + pyrazolopyrimidine
3ene, 2v4l, 2a4z, 2a5u, 1e7u, 1e7v, 1e8w, 1e8y, 1e8z, 1e90, 1e8x, 3tls, 3apc, 3apd, 3apf, 3s2a, 3r7q, 3r7r, 3p2b, 3mjw, 3nzs, 3nzu, 3qaq, 3qar, 3zvv, 3zw3, 3sd5, 3t8m, 3tl5, 4anu, 4anv, 4anw, 4anx, 4aof, 4dk5, 4f1s, 4fa6, 4fad, 4fhj, 4fhk, 4fjy, 4fjz, 4flh, 4ful, 4g11, 4gb9, 4hle, 4hvb, 4j6i - hTI-PI3K p110γ + inhibitor
3tjp, 4ezj, 4ezk, 4ezl, 4kz0, 4kzc - hTI-PI3K p110γ (mutant) + inhibitor
3dpd – hTI-PI3K p110γ + oxazines inhibitor
3dbs – hTI-PI3K p110γ+ GDC0941
3csf, 3cst – hTI-PI3K p110γ + organourethenium inhibitor
2chw, 2chx, 2chz – hTI-PI3K p110γ + PIK-39 inhibitor
3oaw, 3ml9, 3ml8, 3l17, 3l16, 3l13, 3pre, 3prz, 3ps6, 3qjz, 3qk0 – hTI-PI3K p110γ + PI3K/mTOR dual inhibitor
1he8 - hTI-PI3K p110γ + transforming protein P21/H-RAS-1 effector domain

Class I p110δ

2x38 – hTI-PI3K p110δ + IC87114
2wxf, 2wxg, 2wxh, 2wxi, 2wxj, 2wxk, 2wxl, 2wxm, 2wxn, 2wxo, 2wxp, 2wxq, 2wxr, 4ajw – hTI-PI3K p110δ + inhibitors

Class II

2wwe – hPI3KIIγ PHOX homology domain
2ar5, 2iwl, 2rea, 2red – hPI3KII PX domain
2b3r - hPI3KII C2 domain

Class III

2x6f, 2x6h, 2x6j, 2x6k, 2x6i – PI3KIII + inhibitors – Drosophila melanogaster
3ls8 – hPI3KIII + inhibitor
3ihy – hPI3KIII

Additional Resources

  • See: Cancer For Additional Proteins involved in the disease.
  • See: Oncogenes for Additional examples of oncogenes and tumor suppressor genes.


References

  1. Djordjevic S, Driscoll PC. Structural insight into substrate specificity and regulatory mechanisms of phosphoinositide 3-kinases. Trends Biochem Sci. 2002 Aug;27(8):426-32. PMID:12151228
  2. 2.0 2.1 2.2 Wymann MP, Pirola L. Structure and function of phosphoinositide 3-kinases. Biochim Biophys Acta. 1998 Dec 8;1436(1-2):127-50. PMID:9838078
  3. 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
  4. Bi L, Okabe I, Bernard DJ, Wynshaw-Boris A, Nussbaum RL. Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110alpha subunit of phosphoinositide 3-kinase. J Biol Chem. 1999 Apr 16;274(16):10963-8. PMID:10196176
  5. 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
  6. Stephens LR, Hughes KT, Irvine RF. Pathway of phosphatidylinositol(3,4,5)-trisphosphate synthesis in activated neutrophils. Nature. 1991 May 2;351(6321):33-9. PMID:1851250 doi:http://dx.doi.org/10.1038/351033a0
  7. Hoedemaeker FJ, Siegal G, Roe SM, Driscoll PC, Abrahams JP. Crystal structure of the C-terminal SH2 domain of the p85alpha regulatory subunit of phosphoinositide 3-kinase: an SH2 domain mimicking its own substrate. J Mol Biol. 1999 Oct 1;292(4):763-70. PMID:10525402 doi:http://dx.doi.org/10.1006/jmbi.1999.3111


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