Akt/PKB信號通路

Akt信號通路或者PI3K-Akt信號通路是促進響應胞外信號的信號轉導途徑。涉及到的核心蛋白是PI3K (磷脂酰肌醇 3-激酶) 和Akt(蛋白激酶B)。

一種生長因子的初始刺激引起細胞表面受體的活化和PI3K的磷酸化。活化的PI3K進一步磷酸化細胞膜上的脂質，形成第二信使PIP3(磷脂酰肌醇-3,4,5-三磷酸)。 Akt，一種絲氨酸/蘇氨酸激酶，通過與這些磷脂酰肌醇的對接位點的相互作用被募集到細胞膜上。^[1] 活化的Akt通過磷酸化一系列胞內蛋白介導下游響應，包括細胞存活，細胞生長，增殖，細胞遷移和血管形成。Akt信號通路在所有高等真核生物細胞內存在並且高度保守。^[2]

PI3K活化

PI3K有很多種類別，不過只有第I類能夠響應生長刺激而磷酸化脂質。I類的PI3K是異源二聚體，其亞基為p85（調控）與p110（催化）。這兩個亞基是按照分子量命名的。^[3]

這一信號通路可以被很多信號所激活，包括激素，生長因子和胞外基質的成分。^[4]胞外的配體結合到細胞膜上的RTK之後，促進受體二聚化和胞內作用域酪氨酸殘基上的交叉磷酸化。調控亞基p85通過SH2作用域結合到磷酸化的酪氨酸殘基上。它會進而募集催化亞基p110以形成具有完全活性的PI3K。若不然，銜接分子Grb2結合到RTK的磷酸-YXN模體上並通過GAB支架蛋白募集p85。^[5]

p110亞基也可以不依賴於p85被募集。比如，Brb2也可以結合到Ras-GEF Sos1上，並且活化Ras。Ras-GTP進而結合PI3K的p110亞基。其他的銜接分子，比如IRS，也可以活化p110。 ^[6]

PI3K也可以通過G蛋白βγ二聚體被GPCR活化。另外，Gα亞基會活化Src依賴的整聯蛋白，進而活化PI3K。 ^[7]

磷脂酰肌醇的形成

活化的PI3K催化磷酸基團到磷酸肌醇的肌醇環上的3'-OH位置的加成反應，反應有三種脂質產物， PI(3)P, PI(3,4)P₂ 和 PI(3,4,5)P₃:

磷脂酰肌醇(PI) →3-磷酸磷脂酰肌醇(PI(4)P) →3，4-二磷酸磷脂酰肌醇(PI(4,5)P₂) → 3,4,5-三磷酸磷脂酰肌醇。 ^[8]

這些磷酸化的脂質被錨定在細胞膜上，並且可以直接結合細胞內包含PH或FYVE結構域的蛋白。比如說，三磷酸形式 (PI(3,4,5)P₃) 結合Akt和PDK1，這導致它們在細胞膜附近的積累。 ^[1]^[9]

PI3K路徑中的脂磷酸酶PTEN(Phosphatase and tensin homolog)會對磷脂酰肌醇(Phosphatidylinositol)進行調控，PTEN會降解PIP3(Phosphatidylinositol-3,4,5-trisphosphate)，使PIP3轉化為PIP2(Phosphatidylinositol 4,5-bisphosphate)，並且，PTEN的喪失或失活將可能導向惡性腫瘤的產生，因此PTEN對於維持PI3K路徑的正常作用有其重要性。^[10]

Akt的活化

Akt以非活化構象駐留在細胞質中，直到細胞被激活，Akt易位到細胞膜上Akt的PH作用域對於第二信使PI(3,4,5)P3相比其他的磷脂酰肌醇具有更高的親和力。^[11]因此PI3K的活性對於Akt的易位的必要的。與PI(3,4,5)P3的作用導致了構象改變以及磷酸化位點Thr308對激酶位點和C端的Ser473殘基的暴露。PDK1在T308位點的磷酸化導致Akt被部分活化。完全的活化需要S473位點的磷酸化，它是由一系列蛋白，包括PDK2，ILK，^[1]mTORC 和 DNA-PK所催化的。^[6]^[12] Ser473磷酸化的調節還沒有被完全理解，但是可能也被Thr308磷酸化之後的子磷酸化所影響。刺激之後，PiP3上升，Akt活性通過絲氨酸/蘇氨酸磷酸酶的去磷酸化所削弱。^[4]

不依賴於PI3K的活化

儘管PI3K是Akt活化的主要模式，其他酪氨酸或者絲氨酸/蘇氨酸激酶也可以在生長因子、免疫或者DNA損傷的作用下直接激活Akt。它們甚至可以在PI3K活性被抑制的情況下作用。^[13] 另有研究顯示Akt可以被熱休克^[14] 或胞內鈣濃度的增加所激活。^[12]^[15]

More information 激酶, Akt磷酸化位點 ...

激酶	Akt磷酸化位點	細節
Activated CDC42 kinase 1 (Ack1)	Tyr176	Akt傾向於結合磷脂酸（PA）而不是 PIP₃ 從而能移位到細胞膜上。^[16]
Src	Tyr315, Tyr326	需要Src SH3作用域與Akt C端的富脯氨酸區域的相互作用。^[17]
Protein tyrosine kinase 6 (PTK6)	Tyr215, Tyr315和Tyr326	在表皮生長因子(EGF)的作用下激活Akt。^[18]
IκB kinase ε (IKKε)	Ser137, Thr308和 Ser473	獨立於PH作用域，PI3K,PDK1和mTOR。 ^[19]
TANK-binding kinase 1 (TBK1)	Thr195, Ser378和 Ser473	巨噬細胞中Toll樣受體的激活。^[20]
DNA-dependent protein kinase (DNA-PK)	Ser473	由電離輻射致使的DNA雙鏈斷裂所激活。^[21]

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蛋白激酶B
PI3K/AKT/mTOR信號通路
信號轉導

[1]
Osaki M, Oshimura M, Ito H. The PI3K-Akt pathway: Its functions and alterations in human cancer. Apoptosis. 2004, 9 (6): 667–676. PMID 15505410. doi:10.1023/B:APPT.0000045801.15585.dd.
[2]
Manning BD, Cantley LC. AKT/PKB Signaling: Navigating Downstream. Cell. 2007, 129 (7): 1261–1274. PMC 2756685 . PMID 17604717. doi:10.1016/j.cell.2007.06.009.
[3]
Cantrell DA. Phosphoinositide 3-kinase signalling pathways. J Cell Sci. 2001, 114: 1439–1445. PMID 11282020.
[4]
Nicholson KM, Anderson NG. The protein kinase B/Akt signalling pathway in human malignancy. Cellular Signalling. 2002, 14 (5): 381–395. PMID 11882383. doi:10.1016/S0898-6568(01)00271-6.
[5]
Castellano E, Downward J. RAS Interaction with PI3K. Genes Cancer. 2011, 2 (3): 261–74. PMC 3128635 . PMID 21779497. doi:10.1177/1947601911408079.
[6]
Hemmings BA, Restuccia DF. PI3K-PKB/Akt Pathway. Cold Spring Harb Perspect Biol. 2012, 4 (9): a011189. PMC 3428770 . PMID 22952397. doi:10.1101/cshperspect.a011189.
[7]
New DC, Wong YH. Molecular mechanisms mediating the G protein-coupled receptor regulation of cell cycle progression. J Mol Signall. 2007, 2 (2). PMC 1808056 . PMID 17319972. doi:10.1186/1750-2187-2-2.
[8]
Fruman DA, Meyers RE, Cantley LC. Phosphoinositide Kinases. Annu Rev Biochem. 1998, 67: 481–507. PMID 9759495. doi:10.1146/annurev.biochem.67.1.481.
[9]
Cantley LC. The Phosphoinositide 3-Kinase Pathway. Science. 2002, 296 (5573): 1655–1657. PMID 12040186. doi:10.1126/science.296.5573.1655.
[10]
王健珍、王慧虹、沈家瑞、施美份、殷本惠、張立青、陳秋蘭、程中玉、劉昭麟、劉淑芬、鐘渙、嚴錦城(譯)(2015)。藥理學原理：以病態生理學為基礎的藥物治療(原作者：David E. Golan · Armen H. Tashjian, Jr. and Ehrin J. Armstrong · April W. Armstrong)，頁568，699-701，709-710。藝軒圖書出版社。
[11]
Miao B, Skidan I, Yang J, Lugovskoy A, Reibarkh M, Long K, Brazell T, Durugkar KA, Maki J, Ramana CV, Schaffhausen B, Wagner G, Torchilin V, Yuan J, Degterev A. Small molecule inhibition of phosphatidylinositol-3,4,5-triphosphate (PIP3) binding to pleckstrin homology domains. Proc. Natl. Acad. Sci. USA. 2010, 107 (46): 20126–20131. PMC 2993381 . PMID 21041639. doi:10.1073/pnas.1004522107.
[12]
Vanhaesebroeck B, Alessi DR. The PI3K-PDK1 connection: more than just a road to PKB. Biochem J. 2000, 346: 561–576. PMC 1220886 . PMID 10698680. doi:10.1042/0264-6021:3460561.
[13]
Mahajan K, Mahajam NP. PI3K-Independent AKT activation in Cancers: A Treasure Trove for Novel Therapeutics. J Cell Physiol. 2012, 227: 3178–3184. PMC 3358464 . PMID 22307544. doi:10.1002/jcp.24065.
[14]
M Shaw; P Cohen; D R Alessi. The activation of protein kinase B by H2O2 or heat shock is mediated by phosphoinositide 3-kinase and not by mitogen-activated protein kinase-activated protein kinase-2. Biochem J. 1998, 336 (1): 241–246. PMC 1219864 . PMID 9806907.
[15]
Soderling TR. The Ca-calmodulin-dependent protein kinase cascade. Trends Biochem. Sci. 1999, 24 (6): 232–236. PMID 10366852. doi:10.1016/S0968-0004(99)01383-3.
[16]
Mahajan K, Mahajam NP. Shepherding AKT and androgen receptor by Ack1 tyrosine kinase. J Cell Physiol. 2010, 224 (2): 327–33. PMC 3953130 . PMID 20432460. doi:10.1002/jcp.22162.
[17]
Jiang T1 & Qiu Y. Interaction between Src and a C-terminal proline-rich motif of Akt is required for Akt activation. J Biol Chem. 2003, 278 (18): 15789–93. PMID 12600984. doi:10.1074/jbc.M212525200.
[18]
Zheng Y, Peng M, Wang Z, Asara JM, Tyner AL. Protein tyrosine kinase 6 directly phosphorylates AKT and promotes AKT activation in response to epidermal growth factor. Mol Cell Biol. 2010, 30 (17): 4280–92. PMC 2937549 . PMID 20606012. doi:10.1128/MCB.00024-10.
[19]
Guo JP, Coppola D, Cheng JQ. IKBKE protein activates Akt independent of phosphatidylinositol 3-kinase/PDK1/mTORC2 and the pleckstrin homology domain to sustain malignant transformation. J Biol Chem. 2011, 286 (43): 37389–98. PMC 3199486 . PMID 21908616. doi:10.1074/jbc.M111.287433.
[20]
Joung SM, Park ZY, Rani S, Takeuchi O, Akira S, Lee JY. Akt contributes to activation of the TRIF-dependent signaling pathways of TLRs by interacting with TANK-binding kinase 1. J Immunol. 2011, 186 (1): 499–507. PMID 21106850. doi:10.4049/jimmunol.0903534.
[21]
Toulany M, Rodemann HP. Potential of Akt mediated DNA repair in radioresistance of solid tumors overexpressing erbB-PI3K-Akt pathway. Translational Cancer Research. 2013, 2 (3). doi:10.3978/j.issn.2218-676X.2013.04.09.

KEGG Pathway: PI3K-Akt signaling pathway（頁面存檔備份，存於互聯網檔案館）
CST: PI3K/Akt Signaling Resources（頁面存檔備份，存於互聯網檔案館）

[Osaki2004-1] [1]
Osaki M, Oshimura M, Ito H. The PI3K-Akt pathway: Its functions and alterations in human cancer. Apoptosis. 2004, 9 (6): 667–676. PMID 15505410. doi:10.1023/B:APPT.0000045801.15585.dd.

[Manning2007-2] [2]
Manning BD, Cantley LC. AKT/PKB Signaling: Navigating Downstream. Cell. 2007, 129 (7): 1261–1274. PMC 2756685 . PMID 17604717. doi:10.1016/j.cell.2007.06.009.

[Cantrell2001-3] [3]
Cantrell DA. Phosphoinositide 3-kinase signalling pathways. J Cell Sci. 2001, 114: 1439–1445. PMID 11282020.

[Nicholson2002-4] [4]
Nicholson KM, Anderson NG. The protein kinase B/Akt signalling pathway in human malignancy. Cellular Signalling. 2002, 14 (5): 381–395. PMID 11882383. doi:10.1016/S0898-6568(01)00271-6.

[Castellano2011-5] [5]
Castellano E, Downward J. RAS Interaction with PI3K. Genes Cancer. 2011, 2 (3): 261–74. PMC 3128635 . PMID 21779497. doi:10.1177/1947601911408079.

[Hemmings2012-6] [6]
Hemmings BA, Restuccia DF. PI3K-PKB/Akt Pathway. Cold Spring Harb Perspect Biol. 2012, 4 (9): a011189. PMC 3428770 . PMID 22952397. doi:10.1101/cshperspect.a011189.

[New2007-7] [7]
New DC, Wong YH. Molecular mechanisms mediating the G protein-coupled receptor regulation of cell cycle progression. J Mol Signall. 2007, 2 (2). PMC 1808056 . PMID 17319972. doi:10.1186/1750-2187-2-2.

[Fruman1998-8] [8]
Fruman DA, Meyers RE, Cantley LC. Phosphoinositide Kinases. Annu Rev Biochem. 1998, 67: 481–507. PMID 9759495. doi:10.1146/annurev.biochem.67.1.481.

[Cantley2002-9] [9]
Cantley LC. The Phosphoinositide 3-Kinase Pathway. Science. 2002, 296 (5573): 1655–1657. PMID 12040186. doi:10.1126/science.296.5573.1655.

[10] [10]
王健珍、王慧虹、沈家瑞、施美份、殷本惠、張立青、陳秋蘭、程中玉、劉昭麟、劉淑芬、鐘渙、嚴錦城(譯)(2015)。藥理學原理：以病態生理學為基礎的藥物治療(原作者：David E. Golan · Armen H. Tashjian, Jr. and Ehrin J. Armstrong · April W. Armstrong)，頁568，699-701，709-710。藝軒圖書出版社。

[Miao2010-11] [11]
Miao B, Skidan I, Yang J, Lugovskoy A, Reibarkh M, Long K, Brazell T, Durugkar KA, Maki J, Ramana CV, Schaffhausen B, Wagner G, Torchilin V, Yuan J, Degterev A. Small molecule inhibition of phosphatidylinositol-3,4,5-triphosphate (PIP3) binding to pleckstrin homology domains. Proc. Natl. Acad. Sci. USA. 2010, 107 (46): 20126–20131. PMC 2993381 . PMID 21041639. doi:10.1073/pnas.1004522107.

[Vanhaesebroeck2000-12] [12]
Vanhaesebroeck B, Alessi DR. The PI3K-PDK1 connection: more than just a road to PKB. Biochem J. 2000, 346: 561–576. PMC 1220886 . PMID 10698680. doi:10.1042/0264-6021:3460561.

[Mahajan2012-13] [13]
Mahajan K, Mahajam NP. PI3K-Independent AKT activation in Cancers: A Treasure Trove for Novel Therapeutics. J Cell Physiol. 2012, 227: 3178–3184. PMC 3358464 . PMID 22307544. doi:10.1002/jcp.24065.

[Shaw1998-14] [14]
M Shaw; P Cohen; D R Alessi. The activation of protein kinase B by H2O2 or heat shock is mediated by phosphoinositide 3-kinase and not by mitogen-activated protein kinase-activated protein kinase-2. Biochem J. 1998, 336 (1): 241–246. PMC 1219864 . PMID 9806907.

[Soderling1999-15] [15]
Soderling TR. The Ca-calmodulin-dependent protein kinase cascade. Trends Biochem. Sci. 1999, 24 (6): 232–236. PMID 10366852. doi:10.1016/S0968-0004(99)01383-3.

[Mahajan2010-16] [16]
Mahajan K, Mahajam NP. Shepherding AKT and androgen receptor by Ack1 tyrosine kinase. J Cell Physiol. 2010, 224 (2): 327–33. PMC 3953130 . PMID 20432460. doi:10.1002/jcp.22162.

[Jiang2003-17] [17]
Jiang T1 & Qiu Y. Interaction between Src and a C-terminal proline-rich motif of Akt is required for Akt activation. J Biol Chem. 2003, 278 (18): 15789–93. PMID 12600984. doi:10.1074/jbc.M212525200.

[Zheng2010-18] [18]
Zheng Y, Peng M, Wang Z, Asara JM, Tyner AL. Protein tyrosine kinase 6 directly phosphorylates AKT and promotes AKT activation in response to epidermal growth factor. Mol Cell Biol. 2010, 30 (17): 4280–92. PMC 2937549 . PMID 20606012. doi:10.1128/MCB.00024-10.

[Guo2011-19] [19]
Guo JP, Coppola D, Cheng JQ. IKBKE protein activates Akt independent of phosphatidylinositol 3-kinase/PDK1/mTORC2 and the pleckstrin homology domain to sustain malignant transformation. J Biol Chem. 2011, 286 (43): 37389–98. PMC 3199486 . PMID 21908616. doi:10.1074/jbc.M111.287433.

[Juong2011-20] [20]
Joung SM, Park ZY, Rani S, Takeuchi O, Akira S, Lee JY. Akt contributes to activation of the TRIF-dependent signaling pathways of TLRs by interacting with TANK-binding kinase 1. J Immunol. 2011, 186 (1): 499–507. PMID 21106850. doi:10.4049/jimmunol.0903534.

[Toulany2013-21] [21]
Toulany M, Rodemann HP. Potential of Akt mediated DNA repair in radioresistance of solid tumors overexpressing erbB-PI3K-Akt pathway. Translational Cancer Research. 2013, 2 (3). doi:10.3978/j.issn.2218-676X.2013.04.09.

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Akt/PKB信號通路

PI3K活化

磷脂酰肌醇的形成

Akt的活化

不依賴於PI3K的活化

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Akt/PKB信號通路

PI3K活化

磷脂酰肌醇的形成

Akt的活化

不依賴於PI3K的活化

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作用機制

另見

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