eEF2K

EEF2K
識別子
記号	EEF2K, HSU93850, eEF-2K, eukaryotic elongation factor 2 kinase, CAMKIII, calmodulin-dependent protein kinase III
外部ID	OMIM: 606968 MGI: 1195261 HomoloGene: 7299 GeneCards: EEF2K
遺伝子の位置 (ヒト)
染色体	16番染色体 (ヒト)
終点	22,288,738 bp
遺伝子の位置 (マウス)
染色体	7番染色体 (マウス)
終点	120,506,673 bp
RNA発現パターン
	; ;
	さらなる参照発現データ
遺伝子オントロジー
分子機能	• ヌクレオチド結合; • calcium ion binding; • protein kinase activity; • トランスフェラーゼ活性; • protein serine/threonine kinase activity; • キナーゼ活性; • translation factor activity, RNA binding; • calmodulin binding; • ATP binding; • elongation factor-2 kinase activity;
細胞の構成要素	• 細胞質; • 細胞質基質; • シナプス後肥厚; • 樹状突起スパイン;
生物学的プロセス	• positive regulation of endocytosis; • cellular response to cAMP; • response to ischemia; • negative regulation of apoptotic process; • cellular response to insulin stimulus; • positive regulation of synapse assembly; • translational elongation; • cellular response to calcium ion; • 自己リン酸化; • cellular response to brain-derived neurotrophic factor stimulus; • cellular response to anoxia; • タンパク質リン酸化; • positive regulation of dendritic spine morphogenesis; • regulation of protein autophosphorylation; • response to prolactin; • リン酸化;
	出典:Amigo / QuickGO
オルソログ
	29904
	13631
	ENSG00000103319; ENSG00000284161
	ENSMUSG00000035064
	O00418
	O08796
	NM_013302
	NM_001267710; NM_001267711; NM_007908
	NP_037434
	NP_001254639; NP_001254640; NP_031934
	ウィキデータ
閲覧/編集ヒト	閲覧/編集マウス

eEF2K（eukaryotic elongation factor 2 kinase）は、ヒトではEEF2K遺伝子によってコードされる酵素である^[5]^[6]。CAMKIII（calmodulin-dependent protein kinase III）などの名称でも知られる^[7]。

機能

eEF2Kはカルモジュリンを介したシグナル伝達経路に関与する、高度に保存されたプロテインキナーゼであり、上流の複数のシグナルをタンパク質合成の調節と関連付ける。eEF2KはeEF2をリン酸化し、その機能を阻害する^[5]^[8]。

活性化

eEF2Kの活性は、カルシウムとカルモジュリンに依存している。eEF2Kの活性化は、連続的な2段階の機構で進行する。まず、カルシウム-カルモジュリンが高い親和性で結合してキナーゼドメインを活性化し、Thr348の自己リン酸化を迅速に開始する^[9]^[10]。次の段階では、Thr348の自己リン酸化がキナーゼのコンフォメーション変化を引き起こす。この過程はキナーゼドメインのアロステリックなリン酸結合ポケットへのリン酸化Thr348の結合によって行われていると考えられている。その結果、eEF2Kの基質であるeEF2に対する活性が増大する^[10]。

eEF2KはSer500の自己リン酸化によって、カルシウム非依存的な活性を獲得する。しかし、その活性が維持されるためにはカルモジュリンが酵素に結合したままでなければならない^[9]。

臨床的意義

eEF2Kの活性は多くのがんで増大しており、抗がん治療の有効な標的である可能性がある^[5]^[11]。

eEF2Kは、神経のタンパク質合成の調節を介して、ケタミンの迅速な抗うつ効果に関与している可能性がある^[12]。

がん

eEF2Kの発現は乳がんや膵臓がんなどのがん細胞でアップレギュレーションされていることが多く、細胞の増殖、生存、運動性/遊走、浸潤性や腫瘍形成を促進する^[13]^[14]。

出典

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000103319、ENSG00000284161 - Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000035064 - Ensembl, May 2017
^ Human PubMed Reference:
^ Mouse PubMed Reference:
^ ^a ^b ^c “Entrez Gene: EEF2K eukaryotic elongation factor-2 kinase”. 2022年1月15日閲覧。
^ “Identification of a new class of protein kinases represented by eukaryotic elongation factor-2 kinase”. Proceedings of the National Academy of Sciences of the United States of America 94 (10): 4884–9. (May 1997). Bibcode: 1997PNAS...94.4884R. doi:10.1073/pnas.94.10.4884. PMC 24600. PMID 9144159.
^ “EEF2K Gene (Protein Coding)”. GeneCards. Weizmann Institute of Science. 4 November 2015閲覧。
^ “Phosphorylation of elongation factor 2: a key mechanism regulating gene expression in vertebrates”. The New Biologist 2 (10): 843–50. (Oct 1990). PMID 1964087.
^ ^a ^b “Calcium/calmodulin stimulates the autophosphorylation of elongation factor 2 kinase on Thr-348 and Ser-500 to regulate its activity and calcium dependence”. Biochemistry 51 (11): 2232–45. (Mar 2012). doi:10.1021/bi201788e. PMC 3401519. PMID 22329831.
^ ^a ^b “The molecular mechanism of eukaryotic elongation factor 2 kinase activation”. The Journal of Biological Chemistry 289 (34): 23901–16. (Aug 2014). doi:10.1074/jbc.m114.577148. PMC 4156036. PMID 25012662.
^ “The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation”. Cell 153 (5): 1064–79. (May 2013). doi:10.1016/j.cell.2013.04.055. PMC 4395874. PMID 23706743.
^ “The role of eukaryotic elongation factor 2 kinase in rapid antidepressant action of ketamine”. Biological Psychiatry 73 (12): 1199–203. (Jun 2013). doi:10.1016/j.biopsych.2012.09.006. PMC 3574622. PMID 23062356.
^ “Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumors to doxorubicin in an orthotopic model of breast cancer.”. PLOS ONE 7 (7): e41171. (Mar 20, 2012). Bibcode: 2012PLoSO...741171T. doi:10.1371/journal.pone.0041171. PMC 3401164. PMID 22911754.
^ “Targeting elongation factor-2 kinase (eEF-2K) induces apoptosis in human pancreatic cancer cells.”. Apoptosis 19 (1): 241–58. (Jan 22, 2014). doi:10.1007/s10495-013-0927-2. PMID 24193916.

関連文献

“Identification of the major Mr 100,000 substrate for calmodulin-dependent protein kinase III in mammalian cells as elongation factor-2”. The Journal of Biological Chemistry 262 (36): 17299–303. (Dec 1987). doi:10.1016/S0021-9258(18)45377-X. PMID 3693353.
“Regulation of elongation factor-2 by multisite phosphorylation”. European Journal of Biochemistry 213 (2): 689–99. (Apr 1993). doi:10.1111/j.1432-1033.1993.tb17809.x. PMID 8386634.
“Mapping the functional domains of elongation factor-2 kinase”. Biochemistry 39 (40): 12216–24. (Oct 2000). doi:10.1021/bi0007270. PMID 11015200.
“Phosphorylation of elongation factor-2 kinase on serine 499 by cAMP-dependent protein kinase induces Ca2+/calmodulin-independent activity”. The Biochemical Journal 353 (Pt 3): 621–6. (Feb 2001). doi:10.1042/0264-6021:3530621. PMC 1221608. PMID 11171059.
“A novel method to identify protein kinase substrates: eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta”. The EMBO Journal 20 (16): 4360–9. (Aug 2001). doi:10.1093/emboj/20.16.4360. PMC 125581. PMID 11500363.
“Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase”. The EMBO Journal 20 (16): 4370–9. (Aug 2001). doi:10.1093/emboj/20.16.4370. PMC 125559. PMID 11500364.
“Detection of anti-elongation factor 2 kinase (calmodulin-dependent protein kinase III) antibodies in patients with systemic lupus erythematosus”. Biochemical and Biophysical Research Communications 293 (3): 1073–6. (May 2002). doi:10.1016/S0006-291X(02)00324-8. PMID 12051769.
“Expressed sequence tag analysis of human RPE/choroid for the NEIBank Project: over 6000 non-redundant transcripts, novel genes and splice variants”. Molecular Vision 8: 205–20. (Jun 2002). PMID 12107410.
“Stress-induced regulation of eukaryotic elongation factor 2 kinase by SB 203580-sensitive and -insensitive pathways”. The Biochemical Journal 367 (Pt 2): 525–32. (Oct 2002). doi:10.1042/BJ20020916. PMC 1222910. PMID 12171600.
“Stimulation of the AMP-activated protein kinase leads to activation of eukaryotic elongation factor 2 kinase and to its phosphorylation at a novel site, serine 398”. The Journal of Biological Chemistry 279 (13): 12220–31. (Mar 2004). doi:10.1074/jbc.M309773200. PMID 14709557.
“A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin”. Molecular and Cellular Biology 24 (7): 2986–97. (Apr 2004). doi:10.1128/MCB.24.7.2986-2997.2004. PMC 371112. PMID 15024086.
“Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry”. Analytical Chemistry 76 (10): 2763–72. (May 2004). doi:10.1021/ac035352d. PMID 15144186.
“Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain”. The FEBS Journal 272 (16): 4211–20. (Aug 2005). doi:10.1111/j.1742-4658.2005.04833.x. PMID 16098202.
“Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes”. Genome Research 16 (1): 55–65. (Jan 2006). doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
“Elongation factor-2 kinase: its role in protein synthesis and autophagy”. Autophagy 2 (4): 294–6. (2007). doi:10.4161/auto.2857. PMID 16921268.
“A probability-based approach for high-throughput protein phosphorylation analysis and site localization”. Nature Biotechnology 24 (10): 1285–92. (Oct 2006). doi:10.1038/nbt1240. PMID 16964243.
“Global, in vivo, and site-specific phosphorylation dynamics in signaling networks”. Cell 127 (3): 635–48. (Nov 2006). doi:10.1016/j.cell.2006.09.026. PMID 17081983.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000103319、ENSG00000284161 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000035064 - Ensembl, May 2017

[3] Human PubMed Reference:

[4] Mouse PubMed Reference:

[entrez-5] “Entrez Gene: EEF2K eukaryotic elongation factor-2 kinase”. 2022年1月15日閲覧。

[pmid9144159-6] “Identification of a new class of protein kinases represented by eukaryotic elongation factor-2 kinase”. Proceedings of the National Academy of Sciences of the United States of America 94 (10): 4884–9. (May 1997). Bibcode: 1997PNAS...94.4884R. doi:10.1073/pnas.94.10.4884. PMC 24600. PMID 9144159.

[GeneCards-7] “EEF2K Gene (Protein Coding)”. GeneCards. Weizmann Institute of Science. 4 November 2015閲覧。

[Ryazanov_1990-8] “Phosphorylation of elongation factor 2: a key mechanism regulating gene expression in vertebrates”. The New Biologist 2 (10): 843–50. (Oct 1990). PMID 1964087.

[Tavares_2012-9] “Calcium/calmodulin stimulates the autophosphorylation of elongation factor 2 kinase on Thr-348 and Ser-500 to regulate its activity and calcium dependence”. Biochemistry 51 (11): 2232–45. (Mar 2012). doi:10.1021/bi201788e. PMC 3401519. PMID 22329831.

[tavares_2014-10] “The molecular mechanism of eukaryotic elongation factor 2 kinase activation”. The Journal of Biological Chemistry 289 (34): 23901–16. (Aug 2014). doi:10.1074/jbc.m114.577148. PMC 4156036. PMID 25012662.

[pmid23706743-11] “The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation”. Cell 153 (5): 1064–79. (May 2013). doi:10.1016/j.cell.2013.04.055. PMC 4395874. PMID 23706743.

[Monteggia_2013-12] “The role of eukaryotic elongation factor 2 kinase in rapid antidepressant action of ketamine”. Biological Psychiatry 73 (12): 1199–203. (Jun 2013). doi:10.1016/j.biopsych.2012.09.006. PMC 3574622. PMID 23062356.

[Tekedereli_2012-13] “Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumors to doxorubicin in an orthotopic model of breast cancer.”. PLOS ONE 7 (7): e41171. (Mar 20, 2012). Bibcode: 2012PLoSO...741171T. doi:10.1371/journal.pone.0041171. PMC 3401164. PMID 22911754.

[ashour_2014-14] “Targeting elongation factor-2 kinase (eEF-2K) induces apoptosis in human pancreatic cancer cells.”. Apoptosis 19 (1): 241–58. (Jan 22, 2014). doi:10.1007/s10495-013-0927-2. PMID 24193916.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]