PI3キナーゼ（英: Phosphoinositide 3-kinase, PI3K、EC 2.7.1.137）は、イノシトールリン脂質のイノシトール環3位のヒドロキシル基（-OH基）のリン酸化を行う酵素である[1]。イノシトールリン脂質は真核生物の細胞膜を構成する成分の一つであり、PI3Kをはじめとしたキナーゼ（リン酸化酵素）の触媒作用を受けてホスファチジルイノシトール3,4,5-三リン酸 PtdIns(3,4,5)P3となり、プロテインキナーゼB（PKB）/Aktを活性化を起こす。このシグナル伝達経路はPI3キナーゼ-Akt経路と呼ばれ、様々な生理作用の発現に関与する。特にインスリンの分泌促進に深く関与することから[2]、新たな糖尿病薬の開発が示唆されている[3]。
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目次
- 1 分類
- 1.1 クラスI
- 1.2 クラスII・クラスIII
- 2 活性化経路
- 3 機能
- 4 阻害薬
- 5 出典
- 6 参考文献
- 7 外部リンク
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分類
PI3キナーゼは構造によりクラスI・クラスIIおよびクラスIIIの3つのクラスに分類される。
クラスI
クラスI PI3Kはヘテロ二量体であり、シグナル伝達において重要な役割を果たす。これらはアミノ酸配列の相同性からクラスIAとクラスIBにさらに分けられる。クラスIAは p110α、β およびδからなり、調節サブユニットであるp85α、p55α、p50α、p85βおよびp55γと結合している。これらの調節サブユニットのうちp85αの発現が最も高い。p85α、p55α、p50αは同一遺伝子（Pik3r1）のスプライシングバリアントであり、p85βとp55γはそれぞれPik3r2およびPik3r3遺伝子に由来する。クラスIAはPKBの活性化に関与している。一方、クラスIB PI3Kであるp110γは哺乳類においてのみ発現が見られ、Gタンパク質のβγサブユニットやp101によってその機能を調節される。クラスIBのPI3キナーゼは主にGタンパク質共役受容体（GPCR）からの刺激により活性化され、PtdIns(3,4)P2のリン酸化により産生されたPtdIns(3,4,5)P3は細胞内情報伝達機構においてセカンドメッセンジャーとして機能する。
クラスII・クラスIII
クラスIIにはα、βおよびγの4つが存在するが、いずれも調節サブユニットを有さず単量体で酵素活性を示す。クラスIと比較してPtdInsとPtdIns(4)Pに対する基質特異性が高い。クラスIIの機能や活性化機構についてはまだ議論の余地がある。
また、クラスIII PI3KはPtdInsからPtdIns(3)Pを産生し機能的にはクラスIIに近いが、構造的にはクラスIにより類似しておりヘテロ二量体を形成して機能する。クラスIII PI3Kはタンパク質輸送などに関与している。
活性化経路
細胞に何らかの刺激が入るとTyr-X-X-Met（YXXM、X=任意のアミノ酸）モチーフを有する分子に対して調節サブユニットであるp85がSH2ドメインを介して結合する。調節サブユニットは2つのプロリンに富んだ領域（PRMモチーフ）を有しており、p110との結合に関与している[4]。活性化したPI3Kは細胞膜においてPtdIns(3,4,5)P3を産生する反応に関与するが、PKBを活性化する経路にはPtdIns(3,4,5)P3がPKBを活性化する直接的な経路と間接的経路が存在する。間接的経路においてはPtdIns(3,4,5)P3がPDK1（3-phosphoinositide-dependent protein kinase-1）と呼ばれるプロテインキナーゼをリクルートし、PKBのリン酸化を行う。さらにPDK2によるPKBのカルボキシル基側末端側ドメインのリン酸化も行われ、PKBは細胞膜から遊離する。
機能
PI3Kの機能はイノシトールリン脂質をリン酸化することにより、3位がリン酸化されたホスファチジルイノシトールを生成する反応を触媒することである。この反応による生成物としてPtdIns(3)P、PtdIns(3,4)P2、PtdIns(3,5)2、PtdIns(3,4,5)P3が挙げられる。PI3Kの活性化はその下流にある分子を介して細胞分化・増殖や代謝、細胞遊走、細胞骨格の再構築など多様な生物活性を引き起こすことが知られている。インスリン受容体により活性化されたPI3Kは特に細胞へのグルコースの取り込みやタンパク質およびグリコーゲンの合成に関与している。PtdIns(3,4,5)P3をはじめとしたPI3K産物はPKBやプロテインキナーゼδ1などのプレクストリン相同ドメイン（PHドメイン）、PXドメイン、FYVEドメインなどの配列を持つタンパク質に対して結合し下流にシグナルを伝えることが知られる[5][6]。p110αおよびβは全ての細胞において発現しており、遺伝子工学的な手法によりこれらの遺伝子を欠失させたマウス（ノックアウト（KO）マウス）は胎生致死となることが報告されている[7][8]。p110γは好中球やマクロファージの遊走[9][10]や肥満細胞の脱顆粒反応[11]に関与している。癌細胞においてはクラスIAのp110αに変異が生じていることがあり、酵素活性の上昇が見られる。PTENはPtdIns(3,4,5)P3を脱リン酸化する酵素であり、PI3Kの機能に対して拮抗的に働くことにより抗癌化作用を示す。また、p110δは主に白血球などの免疫系細胞において発現がみられる。
阻害薬
PI3K阻害薬としてワートマニン（Wortmannin）やLY294002などの薬物が存在するが高濃度で生体に投与した際に種々の毒性を発現することが知られている。近年では新規PI3K阻害薬であるAS605240やZSTK474、PI3Kδ特異的阻害薬であるIC486068やIC87114は毒性が少ないことから治療薬としての応用が検討されている。
出典
- 今堀 和友、山川 民夫 編集 『生化学辞典 第4版』東京化学同人 2007年 ISBN 978-4-8079-0670-3
- Gomperts BD, Kramer IM and Tatham PE 原著『シグナル伝達』メディカル・サイエンス・インターナショナル 2004年 ISBN 4-89592-369-X
参考文献
- ^ Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J, Katso R, Driscoll PC, Woscholski R, Parker PJ and Waterfield MD.(2001)"Synthesis and function of 3-phosphorylated inositol lipids."Annu.Rev.Biochem. 70,535-602. PMID 11395417
- ^ Kaneko, Kazuma; Ueki, Kohjiro; Takahashi, Noriko; Hashimoto, Shinji; Okamoto, Masayuki; Awazawa, Motoharu; Okazaki, Yukiko; Ohsugi, Mitsuru; Inabe, Kazunori; Umehara, Toshihiro; Yoshida, Masashi; Kakei, Masafumi; Kitamura, Tadahiro; Luo, Ji; Kulkarni, Rohit N.; Kahn, C. Ronald; Kasai, Haruo; Cantley, Lewis C.; Kadowaki, Takashi (2010-12-01) "Class IA Phosphatidylinositol 3-Kinase in Pancreatic β Cells Controls Insulin Secretion by Multiple Mechanisms" Cell Metabolism 12(6):619-632, doi:10.1016/j.cmet.2010.11.005
- ^ 日本放送協会、2010年12月6日「糖尿病 関わるたんぱく質特定」『NHKニュース』2010年12月6日参照
- ^ Otsu M, Hiles I, Gout I, Fry MJ, Ruiz-Larrea F, Panayotou G, Thompson A, Dhand R, Hsuan J, Totty N, et al.(1991)"Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle-T/pp60c-src complexes, and PI3-kinase."Cell. 65, 91-104. PMID 1707345
- ^ Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, Gaffney PR, Reese CB, McCormick F, Tempst P, Coadwell J and Hawkins PT.(1998)"Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B."Science., 279, 710-14. PMID 9445477
- ^ Anderson KE, Coadwell J, Stephens LR and Hawkins PT.(1998)"Translocation of PDK-1 to the plasma membrane is important in allowing PDK-1 to activate protein kinase B."Curr.Biol. 8,684-91. PMID 9637919
- ^ Bi L, Okabe I, Bernard DJ, Wynshaw-Boris A and Nussbaum RL.(1999)"Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110alpha subunit of phosphoinositide 3-kinase."J.Biol.Chem. 274,10963-8. PMID 10196176
- ^ Bi L, Okabe I, Bernard DJ and Nussbaum RL.(2002)"Early embryonic lethality in mice deficient in the p110beta catalytic subunit of PI 3-kinase."Mamm.Genome. 13,169-72. PMID 11919689
- ^ Sasaki T, Irie-Sasaki J, Jones RG, Oliveira-dos-Santos AJ, Stanford WL, Bolon B, Wakeham A, Itie A, Bouchard D, Kozieradzki I, Joza N, Mak TW, Ohashi PS, Suzuki A and Penninger JM.(2000)"Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration."Science. 287,1040-6. PMID 10669416
- ^ Del Prete A, Vermi W, Dander E, Otero K, Barberis L, Luini W, Bernasconi S, Sironi M, Santoro A, Garlanda C, Facchetti F, Wymann MP, Vecchi A, Hirsch E, Mantovani A and Sozzani S.(2004)"Defective dendritic cell migration and activation of adaptive immunity in PI3Kgamma-deficient mice."EMBO J. 23,3505-15. PMID 15318168
- ^ Laffargue M, Calvez R, Finan P, Trifilieff A, Barbier M, Altruda F, Hirsch E and Wymann MP.(2002)"Phosphoinositide 3-kinase gamma is an essential amplifier of mast cell function."Immunity. 16,441-51. PMID 11911828
外部リンク
- PI3K / Akt Signaling（日本語）
| Phosphatidylinositol 3- and 4-kinase |
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| 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 |
| SCOP |
3gmm |
| SUPERFAMILY |
3gmm |
| OPM superfamily |
302 |
| OPM protein |
3ml9 |
| Available protein structures: |
| Pfam |
structures |
| PDB |
RCSB PDB; PDBe |
| PDBsum |
structure summary |
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Phosphatidylinositide 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]
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Contents
- 1 Discovery
- 2 Classes
- 2.1 Class I
- 2.2 Classes II and III
- 3 Human genes
- 4 Mechanism
- 5 Function
- 5.1 Mechanism
- 5.2 Cancers
- 5.3 Learning and memory
- 6 PI 3-kinases as protein kinases
- 7 Inhibition
- 7.1 PI 3-kinases inhibitors as therapeutics
- 8 See also
- 9 References
- 10 Further reading
- 11 External links
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Discovery
The discovery of PI 3-kinases by Lewis Cantley and colleagues began with their identification of a previously unknown phosphoinositide kinase associated with the polyoma middle T protein.[5] They observed unique substrate specificity and chromatographic properties of the products of the lipid kinase, leading to the discovery that this phosphoinositide kinase had the unprecedented ability to phosphorylate phosphoinositides on the 3' position of the inositol ring.[6] Subsequently, Cantley and colleagues demonstrated that in vivo the enzyme prefers PtdIns(4,5)P2 as a substrate, producing the novel phosphoinositide PtdIns(3,4,5)P3.[7]
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.[8]
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, [9] The PI3K is activated by G protein-coupled receptors and tyrosine kinase receptors.[8]
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 is composed of a heterodimer between a p110 catalytic subunit and a p85 regulatory subunit.[10] There are five variants of the p85 regulatory subunit, designated p85α, p55α, p50α, p85β, and p85γ. There are also three variants of the p110 catalytic subunit designated 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 expressed primarily in leukocytes, and it has been suggested that it evolved in parallel with the adaptive immune system. The regulatory p110 and catalytic p110γ subunits comprise the type IB PI3K and are encoded by a single gene each.
The p85 subunits contain SH2 and SH3 domains (Online 'Mendelian Inheritance in Man' (OMIM) 171833). The SH2 domains bind preferentially to phosphorylated tyrosine residues in the amino acid sequence context Y-X-X-M.[11][12]
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 [8] but are more similar to Class I in structure, as they exist as a heterodimers of a catalytic (Vps34) and a regulatory (Vps15/p150) subunits. Class III seems to be primarily involved in the trafficking of proteins and vesicles. There is, however, evidence to show 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 |
EC number |
| class 2 |
PIK3C2A |
PI3K, class 2, alpha polypeptide |
PI3K-C2α |
2.7.1.154 |
| PIK3C2B |
PI3K, class 2, beta polypeptide |
PI3K-C2β |
| PIK3C2G |
PI3K, class 2, gamma polypeptide |
PI3K-C2γ |
| class 3 |
PIK3C3 |
PI3K, class 3 |
Vps34 |
2.7.1.137 |
| class 1 catalytic |
PIK3CA |
PI3K, catalytic, alpha polypeptide |
p110-α |
2.7.1.153 |
| PIK3CB |
PI3K, catalytic, beta polypeptide |
p110-β |
| PIK3CG |
PI3K, catalytic, gamma polypeptide |
p110-γ |
| PIK3CD |
PI3K, catalytic, delta polypeptide |
p110-δ |
| class 1 regulatory |
PIK3R1 |
PI3K, regulatory subunit 1 (alpha) |
p85-α |
N/A |
| 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.
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) as in the PI3K/AKT/mTOR pathway. 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.
Mechanism
The pleckstrin homology domain of AKT binds directly to PtdIns(3,4,5)P3 and PtdIns(3,4)P2, which are produced by activated PI 3-kinase.[13] Since PtdIns(3,4,5)P3 and PtdIns(3,4)P2 are restricted to the plasma membrane, this results in translocation of AKT to the plasma membrane. Likewise, the phosphoinositide-dependent kinase-1 (PDK1 or, rarely referred to as PDPK1) also contains a pleckstrin homology domain that binds directly to PtdIns(3,4,5)P3 and PtdIns(3,4)P2, causing it to also translocate to the plasma membrane upon activation of PI 3-kinase. The colocalization of activated PDK1 and AKT allows AKT to become phosphorylated by PDK1 on threonine 308, leading to partial activation of AKT. Full activation of AKT occurs upon phosphorylation of serine 473 by the TORC2 complex of the mTOR protein kinase. (The nomenclature can be confusing. Note that PDK1 also refers to the unrelated enzyme Pyruvate dehydrogenase kinase, isozyme 1. Similarly, TORC2 also refers to the unrelated transcription factor Transducer of Regulated CREB activity 2, which has recently been renamed CREB-regulated transcription coactivator 2 (CRTC2) to reduce the confusion). 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. The phosphatidylinositol 3-kinase/protein kinase B pathway is stimulated in protection of astrocytes from ceramide-induced apoptosis.[14]
Many other proteins have been identified that are regulated by PtdIns(3,4,5)P3, including Bruton's tyrosine kinase (BTK), General Receptor for Phosphoinositides-1 (GRP1), and the O-linked N-acetylglucosamine (O-GlcNAc) transferase.
Cancers
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 that antagonises PI 3-kinase signaling is absent from many tumours. Hence, PI 3-kinase activity contributes significantly to cellular transformation and the development of cancer.[citation needed]
Learning and memory
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.[15] PI3K is phosphorylated upon NMDA Receptor-dependent CaMKII activity,[16] 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.[17] Notably, the dependence of late-phase LTP expression on PI3K seems to decrease over time.[18]
However, another study found that PI3K inhibitors suppressed the induction, but not the expression, of LTP in mouse hippocampal CA1.[19] The PI3K pathway also recruits many other proteins downstream, including mTOR,[20] GSK3β,[21] and PSD-95.[20] The PI3K-mTOR pathway leads to the phosphorylation of p70S6K, a kinase that facilitates translational activity [22] ,[23] 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.
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.
PI 3-kinases inhibitors as therapeutics
Main article: PI3K inhibitor
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.[citation needed] 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.[citation needed].GDC-0941 is a highly selective inhibitor of p110α with little activity against mTOR.
See also
References
- ^ 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. PMC 2946820. PMID 16647110.
- ^ myo-inositol
- ^ Giese N (2009-03-11). "Cell pathway on overdrive prevents cancer response to dietary restriction". PhysOrg.com. Retrieved 2009-04-22.
- ^ Kalaany NY, Sabatini DM (April 2009). "Tumours with PI3K activation are resistant to dietary restriction". Nature 458 (7239): 725–31. doi:10.1038/nature07782. PMC 2692085. PMID 19279572.
- ^ Whitman M, Kaplan DR, Schaffhausen B, Cantley L, Roberts TM (1985). "Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation". Nature 315 (6016): 239–42. doi:10.1038/315239a0. PMID 2987699.
- ^ Whitman M, Downes CP, Keeler M, Keller T, Cantley L (April 1988). "Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate". Nature 332 (6165): 644–6. doi:10.1038/332644a0. PMID 2833705.
- ^ Auger KR, Serunian LA, Soltoff SP, Libby P, Cantley LC (April 1989). "PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells". Cell 57 (1): 167–75. doi:10.1016/0092-8674(89)90182-7. PMID 2467744.
- ^ 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.
- ^ Okkenhaug K (January 2013). "Signaling by the Phosphoinositide 3-kinase Family in Immune Cells.". Annu. Rev. Immunol. 17 (2): 675–699. PMID 23330955.
- ^ Carpenter CL, Duckworth BC, Auger KR, Cohen B, Schaffhausen BS, Cantley LC (November 1990). "Purification and characterization of phosphoinositide 3-kinase from rat liver". J. Biol. Chem. 265 (32): 19704–11. PMID 2174051.
- ^ Songyang Z, Shoelson SE, Chaudhuri M, et al. (March 1993). "SH2 domains recognize specific phosphopeptide sequences". Cell 72 (5): 767–78. doi:10.1016/0092-8674(93)90404-E. PMID 7680959.
- ^ Yoakim M, Hou W, Songyang Z, Liu Y, Cantley L, Schaffhausen B (September 1994). "Genetic analysis of a phosphatidylinositol 3-kinase SH2 domain reveals determinants of specificity". Mol. Cell. Biol. 14 (9): 5929–38. PMC 359119. PMID 8065326.
- ^ Franke TF, Kaplan DR, Cantley LC, Toker A (January 1997). "Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate". Science 275 (5300): 665–8. doi:10.1126/science.275.5300.665. PMID 9005852.
- ^ Gómez Del Pulgar T, De Ceballos ML, Guzmán M, Velasco G. (September 2002). "Cannabinoids protect astrocytes from ceramide-induced apoptosis through the phosphatidylinositol 3-kinase/protein kinase B pathway". J Biol Chem. 277 (39): 36527–33. doi:10.1074/jbc.M205797200. PMID 12133838.
- ^ 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.
- ^ 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.
- ^ 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". Journal of Neuroscience 22 (9): 3359–65. PMID 11978812.
- ^ 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.
- ^ 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". Journal of Neuroscience 23 (9): 3679–88. PMID 12736339.
- ^ a b 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.
- ^ 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.
- ^ 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.
- ^ 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. PMC 283598. 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. 48 (12): 1149–58. doi:10.1002/mc.20569. PMID 19603422.
- Williams et al.; Berndt, A; Miller, S; Hon, WC; Zhang, X (2009). "Form and flexibility in phosphoinositide 3-kinases". Biochemical Society Transactions 37 (Pt 4): 615–626. doi:10.1042/BST0370615. PMID 19614567.
External links
- Eukaryotic Linear Motif resource motif class MOD_PIKK_1
- Proteopedia Phosphoinositide_3-Kinases to explore the structure in interactive 3D
- PI-3 Kinase at the US National Library of Medicine Medical Subject Headings (MeSH)
- PI3K/Akt Signaling Pathway
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Transferases: phosphorus-containing groups (EC 2.7)
|
|
2.7.1-2.7.4:
phosphotransferase/kinase
(PO4) |
| 2.7.1: OH acceptor |
- Hexo-
- Gluco-
- Fructo-
- Galacto-
- Phosphofructo-
- 1
- Liver
- Muscle
- Platelet
- 2
- Riboflavin
- Shikimate
- Thymidine
- NAD+
- Glycerol
- Pantothenate
- Mevalonate
- Pyruvate
- Deoxycytidine
- PFP
- Diacylglycerol
- Phosphoinositide 3
- Class I PI 3
- Class II PI 3
- Sphingosine
- Glucose-1,6-bisphosphate synthase
|
|
| 2.7.2: COOH acceptor |
- Phosphoglycerate
- Aspartate
|
|
| 2.7.3: N acceptor |
|
|
| 2.7.4: PO4 acceptor |
- Phosphomevalonate
- Adenylate
- Nucleoside-diphosphate
- Uridylate
- Guanylate
- Thiamine-diphosphate
|
|
|
2.7.6: diphosphotransferase
(P2O7) |
- Ribose-phosphate diphosphokinase
- Thiamine diphosphokinase
|
|
2.7.7: nucleotidyltransferase
(PO4-nucleoside) |
| Polymerase |
| DNA polymerase |
- DNA-directed DNA polymerase
- I
- II
- III
- IV
- V
- RNA-directed DNA polymerase
- Reverse transcriptase
- Telomerase
- DNA nucleotidylexotransferase/Terminal deoxynucleotidyl transferase
|
|
| RNA nucleotidyltransferase |
- RNA polymerase/DNA-directed RNA polymerase
- RNA polymerase I
- RNA polymerase II
- RNA polymerase III
- RNA polymerase IV
- Primase
- RNA-dependent RNA polymerase
- PNPase
|
|
|
Phosphorolytic
3' to 5' exoribonuclease |
|
|
| Uridylyltransferase |
- Glucose-1-phosphate uridylyltransferase
- Galactose-1-phosphate uridylyltransferase
|
|
| Guanylyltransferase |
|
|
| Other |
- Recombinase (Integrase)
- Transposase
|
|
|
| 2.7.8: miscellaneous |
| Phosphatidyltransferases |
- CDP-diacylglycerol—glycerol-3-phosphate 3-phosphatidyltransferase
- CDP-diacylglycerol—serine O-phosphatidyltransferase
- CDP-diacylglycerol—inositol 3-phosphatidyltransferase
- CDP-diacylglycerol—choline O-phosphatidyltransferase
|
|
| Glycosyl-1-phosphotransferase |
- N-acetylglucosamine-1-phosphate transferase
|
|
|
2.7.10-2.7.13: protein kinase
(PO4; protein acceptor) |
| 2.7.10: protein-tyrosine |
|
|
| 2.7.11: protein-serine/threonine |
- see serine/threonine-specific protein kinases
|
|
| 2.7.12: protein-dual-specificity |
- see serine/threonine-specific protein kinases
|
|
| 2.7.13: protein-histidine |
- Protein-histidine pros-kinase
- Protein-histidine tele-kinase
- Histidine kinase
|
|
|
- B
- enzm
- 1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
- 2.1
- 2.7.10
- 2.7.11-12
- 3.1
- 4.1
- 5.1
- 6.1-3
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