AKAP9及其与疾病关系的研究进展
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摘要
A型激酶锚定蛋白9(A-kinase anchoring protein9,AKAP9)是A型激酶锚定蛋白家族(AKAPs)中的重要成员。A型激酶锚定蛋白(AKAPs)广泛存在于多种细胞,在底物附近募集不同的信号传导酶,从而将上游激活子和下游作用因子有效的组装在一个大分子信号传导复合物中,整合了共同调节细胞底物的磷酸化的各种信号分子,从而保证了信号传导的特异性和准确性。研究发现,AKAP9可通过和蛋白激酶A(protein kinase A,PKA)直接相连,调控PKA对N-甲基-D-天冬氨酸受体(N-methyl-D-aspartic acid receptor,NMDA)受体的磷酸化,进而参与神经系统功能活动。在心血管系统,AKAP9还可通过与PKA,蛋白磷酸酶1(protein phosphatase 1,PP1)相互作用,调节钾通道的离子流,影响复极化进程,与长QT综合征密切相关。并且对不同病人的基因组大数据筛选发现,AKAP9基因突变存在于多种疾病中,说明AKAP9不仅在正常的生物体中发挥重要作用,而且其异常与多种疾病发生密切相关。因此,本文将着重从AKAP9生理功能及其与疾病之间关系这两方面作一综述。
引文
1 Giri M,Zhang M,Lu Y.Genes associated with Alzheimer's disease:an overview and current status.Clin Interv Aging,2016,11:665~681.
2 Jo YS,Kim MS,Yoo NJ,et al.Frameshift mutations of AKAP9 gene in gastric and colorectal cancers with high microsatellite instability.Pathol Oncol Res,2016,22:587~592.
3 Maltese PE,Orlova N,Krasikova E,et al.Gene-targeted analysis of clinically diagnosed long QT russian families.Int Heart J,2017,58:81~87.
4 T,Scott JD.Signaling through scaffold,anchoring,and adaptorproteins.Science,1998,278:2075~2080.
5 Colledge M,Scott JD.AKAPs:from structure to function.Trends Cell Biol,1999,9:216~221.
6 Dell'Acqua ML,Faux MC,Thorburn J,et al.Membranetargeting sequences on AKAP79 bind phosphatidylinositol-4,5-bisphosphate.EMBO J,1998,17:2246~2260.
7 Redden JM,Dodge-Kafka KL.AKAP phosphatase complexes in the heart.J Cardiovasc Pharmacol,2011,58:354~362.
8 Tang EI,Mruk DD,Cheng CY.MAP/microtubule affinityregulating kinases,microtubule dynamics,and spermatogenesis.J Endocrinol,2013,217:13~23.
9 Wong W,Scott JD.AKAP signalling complexes:focal points in space and time.Nat Rev Mol Cell Biol,2004,5:959~970.
10 Bouguenina H,Salaun D,Mangon A,Muller L,et al.EB1-binding-myomegalin protein complex promotes centrosomal microtubules functions.P Natl Acad Sci USA,2017,114:E10687~E10696.
11 Feliciello A,Cardone L,Garbi C,et al.Yotiao protein,a ligand for the NMDA receptor,binds and targets c AMP-dependent protein kinase II(1).FEBS Lett,1999,464:174~178.
12 Pidoux G,Tasken K.Specificity and spatial dynamics of protein kinase A signaling organized by A-kinase-anchoring proteins.J Mol Endocrinol,2010,44:271~284.
13 Li Y,Chen L,Kass RS,et al.The A-kinase anchoring protein Yotiao facilitates complex formation between adenylyl cyclase type 9 and the IKs potassium channel in heart.JBiol Chem,2012,287:29815~29824.
14 Fakhree MA,Zijlstra N,Raiss CC,et al.The number of alpha-synuclein proteins per vesicle gives insights into its physiological function.Sci Rep,2016,6:30658.
15 Kennedy EJ,Scott JD.Selective disruption of the AKAPsignaling complexes.Methods Mol Biol,2015,1294:137~150.
16 Piggott LA,Bauman AL,Scott JD,et al.The A-kinase anchoring protein Yotiao binds and regulates adenylyl cyclase in brain.Proc Natl Acad Sci USA,2008,105:13835~13840.
17 Dessauer CW.Adenylyl cyclase-A-kinase anchoring protein complexes:the next dimension in c AMP signaling.Mol Pharmacol,2009,76:935~941.
18 Lau C,Takayasu Y,Rodenas-Ruano A,et al.SNAP-25is a target of protein kinase C phosphorylation critical to NMDA receptor trafficking.J Neurosci,2010,30:242~254.
19 Zhou Y,Danbolt NC.Glutamate as a neurotransmitter in the healthy brain.J Neural Transm(Vienna),2014,121:799~817.
20 Tikhonov DB.Ion channels of glutamate receptors:structural modeling.Mol Membr Biol,2007,24:135~147.
21 Lee G,Schwarz TL.Filamin,a synaptic organizer in Drosophila,determines glutamate receptor composition and membrane growth.Elife,2016,5:117~126.
22 Lin JW,Wyszynski M,Madhavan R,et al.Yotiao,a novel protein of neuromuscular junction and brain that interacts with specific splice variants of NMDA receptor subunit NR1.J Neurosci,1998,18:2017~2027.
23 Ciampi R,Knauf JA,Kerler R,et al.Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer.J Clin Invest,2005,115:94~101.
24 Mizusawa Y,Horie M,Wilde AAM.Genetic and clinical advances in congenital long QT syndrome.J Circulation,2014,78:2827~2833.
25 Hsiao PY,Tien HC,Lo CP,et al.Gene mutations in cardiac arrhythmias:a review of recent evidence in ion channelopathies.Appl Clin Genet,2013,6:1~13.
26 Marusyk A,Almendro V,Polyak K.Intra-tumour heterogeneity:a looking glass for cancer?Nat Rev Cancer,2012,12:323~334.
27 Logue MW,Schu M,Vardarajan BN,Farrell.Two rare AKAP9 variants are associated with Alzheimer's disease in African Americans.Alzheimers Dement,2014,10:609~618.
28 Boudoulas KD,Mohler PJ.Beyond membrane channelopathies:alternative mechanisms underlying complex human disease.Acta Pharmacol Sin,2011,32:798~804.
29 Venkatesh D,Mruk D,Herter JM,et al.AKAP9,a regulator of microtubule dynamics,contributes to blood-testis barrier function.Am J Pathol,2016,186:270~284.
2 Jo YS,Kim MS,Yoo NJ,et al.Frameshift mutations of AKAP9 gene in gastric and colorectal cancers with high microsatellite instability.Pathol Oncol Res,2016,22:587~592.
3 Maltese PE,Orlova N,Krasikova E,et al.Gene-targeted analysis of clinically diagnosed long QT russian families.Int Heart J,2017,58:81~87.
4 T,Scott JD.Signaling through scaffold,anchoring,and adaptorproteins.Science,1998,278:2075~2080.
5 Colledge M,Scott JD.AKAPs:from structure to function.Trends Cell Biol,1999,9:216~221.
6 Dell'Acqua ML,Faux MC,Thorburn J,et al.Membranetargeting sequences on AKAP79 bind phosphatidylinositol-4,5-bisphosphate.EMBO J,1998,17:2246~2260.
7 Redden JM,Dodge-Kafka KL.AKAP phosphatase complexes in the heart.J Cardiovasc Pharmacol,2011,58:354~362.
8 Tang EI,Mruk DD,Cheng CY.MAP/microtubule affinityregulating kinases,microtubule dynamics,and spermatogenesis.J Endocrinol,2013,217:13~23.
9 Wong W,Scott JD.AKAP signalling complexes:focal points in space and time.Nat Rev Mol Cell Biol,2004,5:959~970.
10 Bouguenina H,Salaun D,Mangon A,Muller L,et al.EB1-binding-myomegalin protein complex promotes centrosomal microtubules functions.P Natl Acad Sci USA,2017,114:E10687~E10696.
11 Feliciello A,Cardone L,Garbi C,et al.Yotiao protein,a ligand for the NMDA receptor,binds and targets c AMP-dependent protein kinase II(1).FEBS Lett,1999,464:174~178.
12 Pidoux G,Tasken K.Specificity and spatial dynamics of protein kinase A signaling organized by A-kinase-anchoring proteins.J Mol Endocrinol,2010,44:271~284.
13 Li Y,Chen L,Kass RS,et al.The A-kinase anchoring protein Yotiao facilitates complex formation between adenylyl cyclase type 9 and the IKs potassium channel in heart.JBiol Chem,2012,287:29815~29824.
14 Fakhree MA,Zijlstra N,Raiss CC,et al.The number of alpha-synuclein proteins per vesicle gives insights into its physiological function.Sci Rep,2016,6:30658.
15 Kennedy EJ,Scott JD.Selective disruption of the AKAPsignaling complexes.Methods Mol Biol,2015,1294:137~150.
16 Piggott LA,Bauman AL,Scott JD,et al.The A-kinase anchoring protein Yotiao binds and regulates adenylyl cyclase in brain.Proc Natl Acad Sci USA,2008,105:13835~13840.
17 Dessauer CW.Adenylyl cyclase-A-kinase anchoring protein complexes:the next dimension in c AMP signaling.Mol Pharmacol,2009,76:935~941.
18 Lau C,Takayasu Y,Rodenas-Ruano A,et al.SNAP-25is a target of protein kinase C phosphorylation critical to NMDA receptor trafficking.J Neurosci,2010,30:242~254.
19 Zhou Y,Danbolt NC.Glutamate as a neurotransmitter in the healthy brain.J Neural Transm(Vienna),2014,121:799~817.
20 Tikhonov DB.Ion channels of glutamate receptors:structural modeling.Mol Membr Biol,2007,24:135~147.
21 Lee G,Schwarz TL.Filamin,a synaptic organizer in Drosophila,determines glutamate receptor composition and membrane growth.Elife,2016,5:117~126.
22 Lin JW,Wyszynski M,Madhavan R,et al.Yotiao,a novel protein of neuromuscular junction and brain that interacts with specific splice variants of NMDA receptor subunit NR1.J Neurosci,1998,18:2017~2027.
23 Ciampi R,Knauf JA,Kerler R,et al.Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer.J Clin Invest,2005,115:94~101.
24 Mizusawa Y,Horie M,Wilde AAM.Genetic and clinical advances in congenital long QT syndrome.J Circulation,2014,78:2827~2833.
25 Hsiao PY,Tien HC,Lo CP,et al.Gene mutations in cardiac arrhythmias:a review of recent evidence in ion channelopathies.Appl Clin Genet,2013,6:1~13.
26 Marusyk A,Almendro V,Polyak K.Intra-tumour heterogeneity:a looking glass for cancer?Nat Rev Cancer,2012,12:323~334.
27 Logue MW,Schu M,Vardarajan BN,Farrell.Two rare AKAP9 variants are associated with Alzheimer's disease in African Americans.Alzheimers Dement,2014,10:609~618.
28 Boudoulas KD,Mohler PJ.Beyond membrane channelopathies:alternative mechanisms underlying complex human disease.Acta Pharmacol Sin,2011,32:798~804.
29 Venkatesh D,Mruk D,Herter JM,et al.AKAP9,a regulator of microtubule dynamics,contributes to blood-testis barrier function.Am J Pathol,2016,186:270~284.
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