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Phosphatidylinositol 3- and 4-kinase
PI3kinase.png
PI3 Kinase 110 gamma bound to the inhibitor PIK-93 (yellow).[1]
Identifiers
Symbol PI3_PI4_kinase
Pfam PF00454
InterPro IPR000403
SMART SM00146
PROSITE PDOC00710

Phosphoinositide 3-kinases (PI 3-kinases or PI3Ks) are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer.

PI3Ks are a family of related intracellular signal transducer enzymes capable of phosphorylating the 3 position hydroxyl group of the inositol ring of phosphatidylinositol (PtdIns).[2] They are also known as phosphatidylinositol-3-kinases. The pathway, with oncogene PIK3CA and tumor suppressor PTEN (gene) is implicated in insensitivity of cancer tumors to insulin and IGF1, in calorie restriction. [3][4]

Contents

Classes

PI3Ks interact with the IRS (Insulin receptor substrate) in order to regulate glucose uptake through a series of phosphorylation events.

The phosphoinositol-3-kinase family is divided into three different classes: Class I, Class II and Class III. The classifications are based on primary structure, regulation, and in vitro lipid substrate specificity.[5]

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Class I

Class I PI3Ks are responsible for the production of Phosphatidylinositol 3-phosphate (PI(3)P), Phosphatidylinositol (3,4)-bisphosphate (PI(3,4)P2) and Phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3. The PI3K is activated by G-protein coupled receptors and tyrosine kinase receptors.[5]

Class I PI3K are heterodimeric molecules composed of a regulatory and a catalytic subunit; they are further divided between IA and IB subsets on sequence similarity.Class IA PI3K are composed of one of five regulatory p85α, p55α, p50α, p85β or p55γ subunit attached to a p110α, β or δ catalytic subunit. The first three regulatory subunits are all splice variants of the same gene (Pik3r1), the other two being expressed by other genes (Pik3r2 and Pik3r3, p85β and p55γ, respectively). The most highly expressed regulatory subunit is p85α, all three catalytic subunits are expressed by separate genes (Pik3ca, Pik3cb and Pik3cd for p110α, p110β and p110δ, respectively). The first two p110 isoforms (α and β) are expressed in all cells, but p110δ is primarily expressed in leukocytes and it has been suggested it evolved in parallel with the adaptive immune system. The regulatory p101 and catalytic p110γ subunits comprise the type IB PI3K and are encoded by a single gene each.

The majority of the research on PI 3-kinases has focused on the Class I PI 3-kinases. Class I PI 3-kinases are composed of a catalytic subunit known as p110 and a regulatory subunit either related to p85 or p101. The p85 subunits contain SH2 and SH3 domains (Online 'Mendelian Inheritance in Man' (OMIM) 171833).

Classes II and III

Overview of signal transduction pathways involved in apoptosis.

Class II and III PI3K are differentiated from the Class I by their structure and function.

Class II comprises three catalytic isoforms (C2α, C2β, and C2γ), but unlike Classes I and III, no regulatory proteins. Class II catalyse the production of PI(3)P and PI(3,4)P2 from PI; however, little is known about their role in immune cells. C2α and C2β are expressed through the body, however expression of C2γ is limited to hepatocytes. The distinct feature of Class II PI3Ks is the C-terminal C2 domain. This domain lacks critical Asp residues to coordinate binding of Ca2+, which suggests class II PI3Ks bind lipids in a Ca2+ independent manner.

Class III produces only PI(3)P from PI [5] but are more similar to Class I in structure, as they exist as a heterodimers of a catalytic (Vps34) and a regulatory (p150) subunits. Class III seems to be primarily involved in the trafficking of proteins and vesicles. There is, however, evidence that they are able to contribute to the effectiveness of several process important to immune cells, not least phagocytosis.

Human genes

group gene protein aliases
class 2 PIK3C2A PI3K, class 2, alpha polypeptide PI3K-C2α
PIK3C2B PI3K, class 2, beta polypeptide PI3K-C2β
PIK3C2G PI3K, class 2, gamma polypeptide PI3K-C2γ
class 3 PIK3C3 PI3K, class 3 Vps34
catalytic PIK3CA PI3K, catalytic, alpha polypeptide p110-α
PIK3CB PI3K, catalytic, beta polypeptide p110-β
PIK3CG PI3K, catalytic, gamma polypeptide p110-γ
PIK3CD PI3K, catalytic, delta polypeptide p110-δ
regulatory PIK3R1 PI3K, regulatory subunit 1 (alpha) p85-α
PIK3R2 PI3K, regulatory subunit 2 (beta) p85-β
PIK3R3 PI3K, regulatory subunit 3 (gamma) p55-γ
PIK3R4 PI3K, regulatory subunit 4 p150
PIK3R5 PI3K, regulatory subunit 5 p101
PIK3R6 PI3K, regulatory subunit 6 p87

Mechanism

The various 3-phosphorylated phosphoinositides that are produced by PI 3-kinases (PtdIns3P, PtdIns(3,4)P2, PtdIns(3,5)P2 and PtdIns(3,4,5)P3) function in a mechanism by which an assorted group of signalling proteins, containing PX domain, pleckstrin homology domains (PH domains), FYVE domains and other phosphoinositide-binding domains, are recruited to various cellular membranes.

Inhibition

All PI 3-kinases are inhibited by the drugs wortmannin and LY294002, although certain members of the class II PI 3-kinase family show decreased sensitivity.

Function

PI 3-kinases have been linked to an extraordinarily diverse group of cellular functions, including cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. Many of these functions relate to the ability of class I PI 3-kinases to activate protein kinase B (PKB, aka Akt). The class IA PI 3-kinase p110α is mutated in many cancers. Many of these mutations cause the kinase to be more active. The PtdIns(3,4,5)P3 phosphatase PTEN which antagonises PI 3-kinase signalling is absent from many tumours. Hence, PI 3-kinase activity contributes significantly to cellular transformation and the development of cancer. The p110δ and p110γ isoforms regulate different aspects of immune responses. PI 3-kinases are also a key component of the insulin signaling pathway. Hence there is great interest in the role of PI 3-kinase signaling in Diabetes mellitus.

AKT is activated as a result of PI3-kinase activity, because AKT requires the formation of the PtdIns(3,4,5)P3 (or "PIP3") molecule in order to be translocated to the cell membrane. At PIP3, AKT is then phosphorylated by another kinase called phosphoinositide dependent protein kinase 1 (PDPK1), and is thereby activated. (Please do not confuse with the Pyruvate dehydrogenase kinase, isozyme 1 which is also abbreviated as PDK1). The "PI3-k/AKT" signaling pathway has been shown to be required for an extremely diverse array of cellular activities - most notably cellular proliferation and survival.

In addition to AKT and PDK1, one other related serine threonine kinase is bound at the PIP3 molecule created as a result of PI3-kinase activity, SGK.

PI3K has also been implicated in Long term potentiation (LTP). Whether it is required for the expression or the induction of LTP is still debated. In mouse hippocampal CA1 neurons, PI3K is complexed with AMPA Receptors and compartmentalized at the postsynaptic density of glutamatergic synapses[6]. PI3K is phosphorylated upon NMDA Receptor-dependent CaMKII activity[7], and it then facilitates the insertion of AMPA-R GluR1 subunits into the plasma membrane. This suggests that PI3K is required for the expression of LTP. Furthermore, PI3K inhibitors abolished the expression of LTP in rat hippocampal CA1, but do not affect its induction[8]. Notably, the dependence of late-phase LTP expression on PI3K seems to decrease over time[9].

However, another study found that PI3K inhibitors suppressed the induction, but not the expression, of LTP in mouse hippocampal CA1[10]. The PI3K pathway also recruits many other proteins downstream, including mTOR[11], GSK3β[12], and PSD-95[13]. The PI3K-mTOR pathway leads to the phosphorylation of p70S6K, a kinase which facilitates translational activity [14][15] , further suggesting that PI3K is required for the protein-synthesis phase of LTP induction instead.

PI 3-kinases as protein kinases

Many of the PI 3-kinases appear to have a serine/threonine kinase activity in vitro; however, it is unclear whether this has any role in vivo.

In addition to the class I – class III PI 3-kinases there is a group of more distantly related enzymes that are sometimes referred to as class IV PI 3-kinases. The class IV PI 3-kinases family is composed of ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3 related (ATR), DNA-dependent protein kinase (DNA-PK) and mammalian Target Of Rapamycin (mTOR). These members of the PI 3-kinase superfamily are protein serine/threonine kinases.

PI 3-kinases inhibitors as therapeutics

As wortmannin and LY294002 are broad inhibitors against PI 3-kinases and a number of unrelated proteins at higher concentrations they are too toxic to be used as therapeutics. A number of pharmaceutical companies have recently been working on PI 3-kinase isoform specific inhibitors including the class I PI 3-kinase, p110δ isoform specific inhibitors, IC486068 and IC87114, ICOS Corporation.

References

  1. ^ PDB 2chz; Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, Loewith R, Stokoe D, Balla A, Toth B, Balla T, Weiss WA, Williams RL, Shokat KM (May 2006). "A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling". Cell 125 (4): 733–47. doi:10.1016/j.cell.2006.03.035. PMID 16647110.  
  2. ^ myo-inositol
  3. ^ Giese N (2009-03-11). "Cell pathway on overdrive prevents cancer response to dietary restriction". PhysOrg.com. http://www.physorg.com/news156000728.html. Retrieved 2009-04-22.  
  4. ^ Kalaany NY, Sabatini DM (April 2009). "Tumours with PI3K activation are resistant to dietary restriction". Nature 458 (7239): 725–31. doi:10.1038/nature07782. PMID 19279572.  
  5. ^ a b c Leevers SJ, Vanhaesebroeck B, Waterfield MD (April 1999). "Signalling through phosphoinositide 3-kinases: the lipids take centre stage". Current Opinion in Cell Biology 11 (2): 219–25. doi:10.1016/S0955-0674(99)80029-5. PMID 10209156.  
  6. ^ Man HY, Wang Q, Lu WY, et al. (May 2003). "Activation of PI3-kinase is required for AMPA-R insertion during LTP of mEPSCs in cultured hippocampal neurons". Neuron 38 (4): 611–24. doi:10.1016/S0896-6273(03)00228-9. PMID 12765612. http://linkinghub.elsevier.com/retrieve/pii/S0896627303002289.  
  7. ^ Joyal JL, Burks DJ, Pons S, et al. (November 1997). "Calmodulin activates phosphatidylinositol 3-kinase". The Journal of biological chemistry 272 (45): 28183–6. doi:10.1074/jbc.272.45.28183. PMID 9353264. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=9353264.  
  8. ^ Sanna PP, Cammalleri M, Berton F, et al. (May 2002). "Phosphatidylinositol 3-kinase is required for the expression but not for the induction or the maintenance of long-term potentiation in the hippocampal CA1 region". The Journal of neuroscience : the official journal of the Society for Neuroscience 22 (9): 3359–65. doi:20026298. PMID 11978812.  
  9. ^ Karpova A, Sanna PP, Behnisch T (February 2006). "Involvement of multiple phosphatidylinositol 3-kinase-dependent pathways in the persistence of late-phase long term potentiation expression". Neuroscience 137 (3): 833–41. doi:10.1016/j.neuroscience.2005.10.012. PMID 16326012.  
  10. ^ Opazo P, Watabe AM, Grant SG, O'Dell TJ (May 2003). "Phosphatidylinositol 3-kinase regulates the induction of long-term potentiation through extracellular signal-related kinase-independent mechanisms". The Journal of neuroscience : the official journal of the Society for Neuroscience 23 (9): 3679–88. PMID 12736339. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=12736339.  
  11. ^ Yang PC, Yang CH, Huang CC, Hsu KS (February 2008). "Phosphatidylinositol 3-kinase activation is required for stress protocol-induced modification of hippocampal synaptic plasticity". The Journal of biological chemistry 283 (5): 2631–43. doi:10.1074/jbc.M706954200. PMID 18057005.  
  12. ^ Peineau S, Taghibiglou C, Bradley C, et al. (March 2007). "LTP inhibits LTD in the hippocampus via regulation of GSK3beta". Neuron 53 (5): 703–17. doi:10.1016/j.neuron.2007.01.029. PMID 17329210.  
  13. ^ Yang PC, Yang CH, Huang CC, Hsu KS (February 2008). "Phosphatidylinositol 3-kinase activation is required for stress protocol-induced modification of hippocampal synaptic plasticity". The Journal of biological chemistry 283 (5): 2631–43. doi:10.1074/jbc.M706954200. PMID 18057005.  
  14. ^ Toker A, Cantley LC (June 1997). "Signalling through the lipid products of phosphoinositide-3-OH kinase". Nature 387 (6634): 673–6. doi:10.1038/42648. PMID 9192891.  
  15. ^ Cammalleri M, Lütjens R, Berton F, et al. (November 2003). "Time-restricted role for dendritic activation of the mTOR-p70S6K pathway in the induction of late-phase long-term potentiation in the CA1". Proceedings of the National Academy of Sciences of the United States of America 100 (24): 14368–73. doi:10.1073/pnas.2336098100. PMID 14623952.  

Further reading

  • Vanhaesebroeck B, Leevers S, Ahmadi K, Timms J, Katso R, Driscoll P, Woscholski R, Parker P, Waterfield M (2001). "Synthesis and function of 3-phosphorylated inositol lipids". Annu Rev Biochem 70: 535–602. doi:10.1146/annurev.biochem.70.1.535. PMID 11395417.   [1]
  • Schild C, Wirth M, Reichert M, Schmid RM, Saur D, Schneider G (July 2009). "PI3K signaling maintains c-myc expression to regulate transcription of E2F1 in pancreatic cancer cells". Mol. Carcinog.. doi:10.1002/mc.20569. PMID 19603422.  

External links


Redirecting to Phosphoinositide 3-kinase


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