3cqw

Structural highlights

Disease

[AKT1_HUMAN] Defects in AKT1 are a cause of susceptibility to breast cancer (BC) [MIM:114480]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Defects in AKT1 are associated with colorectal cancer (CRC) [MIM:114500]. Note=Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer. Defects in AKT1 are a cause of Proteus syndrome (PROTEUSS) [MIM:176920]. A highly variable, severe disorder of asymmetric and disproportionate overgrowth of body parts, connective tissue nevi, epidermal nevi, dysregulated adipose tissue, and vascular malformations. Many features of Proteus syndrome overlap with other overgrowth syndromes.^{[1] [2]}

Function

[AKT1_HUMAN] AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development. Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity.^{[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27]} AKT1-specific substrates have been recently identified, including palladin (PALLD), which phosphorylation modulates cytoskeletal organization and cell motility; prohibitin (PHB), playing an important role in cell metabolism and proliferation; and CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation.^{[28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52]} [GSK3B_HUMAN] Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1. Requires primed phosphorylation of the majority of its substrates. In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. May also mediate the development of insulin resistance by regulating activation of transcription factors. Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase. In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes. Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin. Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules. MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease. Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair. Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes. Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin. Is necessary for the establishment of neuronal polarity and axon outgrowth. Phosphorylates MARK2, leading to inhibit its activity. Phosphorylates SIK1 at 'Thr-182', leading to sustain its activity. Phosphorylates ZC3HAV1 which enhances its antiviral activity. Phosphorylates SFPQ at 'Thr-687' upon T-cell activation.^{[53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

• Serine/threonine protein kinase 3D structures

References

1. ↑ Landgraf KE, Pilling C, Falke JJ. Molecular mechanism of an oncogenic mutation that alters membrane targeting: Glu17Lys modifies the PIP lipid specificity of the AKT1 PH domain. Biochemistry. 2008 Nov 25;47(47):12260-9. doi: 10.1021/bi801683k. PMID:18954143 doi:10.1021/bi801683k
2. ↑ Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, Turner J, Cannons JL, Bick D, Blakemore L, Blumhorst C, Brockmann K, Calder P, Cherman N, Deardorff MA, Everman DB, Golas G, Greenstein RM, Kato BM, Keppler-Noreuil KM, Kuznetsov SA, Miyamoto RT, Newman K, Ng D, O'Brien K, Rothenberg S, Schwartzentruber DJ, Singhal V, Tirabosco R, Upton J, Wientroub S, Zackai EH, Hoag K, Whitewood-Neal T, Robey PG, Schwartzberg PL, Darling TN, Tosi LL, Mullikin JC, Biesecker LG. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med. 2011 Aug 18;365(7):611-9. doi: 10.1056/NEJMoa1104017. Epub 2011 Jul, 27. PMID:21793738 doi:10.1056/NEJMoa1104017
3. ↑ Coffer PJ, Woodgett JR. Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families. Eur J Biochem. 1991 Oct 15;201(2):475-81. PMID:1718748
4. ↑ Du K, Montminy M. CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem. 1998 Dec 4;273(49):32377-9. PMID:9829964
5. ↑ Walker KS, Deak M, Paterson A, Hudson K, Cohen P, Alessi DR. Activation of protein kinase B beta and gamma isoforms by insulin in vivo and by 3-phosphoinositide-dependent protein kinase-1 in vitro: comparison with protein kinase B alpha. Biochem J. 1998 Apr 1;331 ( Pt 1):299-308. PMID:9512493
6. ↑ Rena G, Guo S, Cichy SC, Unterman TG, Cohen P. Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. J Biol Chem. 1999 Jun 11;274(24):17179-83. PMID:10358075
7. ↑ Zimmermann S, Moelling K. Phosphorylation and regulation of Raf by Akt (protein kinase B). Science. 1999 Nov 26;286(5445):1741-4. PMID:10576742
8. ↑ Koh H, Lee KH, Kim D, Kim S, Kim JW, Chung J. Inhibition of Akt and its anti-apoptotic activities by tumor necrosis factor-induced protein kinase C-related kinase 2 (PRK2) cleavage. J Biol Chem. 2000 Nov 3;275(44):34451-8. PMID:10926925 doi:10.1074/jbc.M001753200
9. ↑ Kim AH, Khursigara G, Sun X, Franke TF, Chao MV. Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol. 2001 Feb;21(3):893-901. PMID:11154276 doi:10.1128/MCB.21.3.893-901.2001
10. ↑ Kane S, Sano H, Liu SC, Asara JM, Lane WS, Garner CC, Lienhard GE. A method to identify serine kinase substrates. Akt phosphorylates a novel adipocyte protein with a Rab GTPase-activating protein (GAP) domain. J Biol Chem. 2002 Jun 21;277(25):22115-8. Epub 2002 May 6. PMID:11994271 doi:10.1074/jbc.C200198200
11. ↑ Fujita N, Sato S, Katayama K, Tsuruo T. Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization. J Biol Chem. 2002 Aug 9;277(32):28706-13. Epub 2002 May 31. PMID:12042314 doi:10.1074/jbc.M203668200
12. ↑ Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell. 2002 Jul;10(1):151-62. PMID:12150915
13. ↑ Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J, Arteaga CL. PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat Med. 2002 Oct;8(10):1145-52. Epub 2002 Sep 16. PMID:12244301 doi:10.1038/nm759
14. ↑ Lennartsson J, Wernstedt C, Engstrom U, Hellman U, Ronnstrand L. Identification of Tyr900 in the kinase domain of c-Kit as a Src-dependent phosphorylation site mediating interaction with c-Crk. Exp Cell Res. 2003 Aug 1;288(1):110-8. PMID:12878163
15. ↑ Enomoto A, Murakami H, Asai N, Morone N, Watanabe T, Kawai K, Murakumo Y, Usukura J, Kaibuchi K, Takahashi M. Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev Cell. 2005 Sep;9(3):389-402. PMID:16139227 doi:S1534-5807(05)00295-9
16. ↑ Srinivas H, Xia D, Moore NL, Uray IP, Kim H, Ma L, Weigel NL, Brown PH, Kurie JM. Akt phosphorylates and suppresses the transactivation of retinoic acid receptor alpha. Biochem J. 2006 May 1;395(3):653-62. PMID:16417524 doi:10.1042/BJ20051794
17. ↑ Heron-Milhavet L, Franckhauser C, Rana V, Berthenet C, Fisher D, Hemmings BA, Fernandez A, Lamb NJ. Only Akt1 is required for proliferation, while Akt2 promotes cell cycle exit through p21 binding. Mol Cell Biol. 2006 Nov;26(22):8267-80. Epub 2006 Sep 18. PMID:16982699 doi:10.1128/MCB.00201-06
18. ↑ Jang SW, Yang SJ, Srinivasan S, Ye K. Akt phosphorylates MstI and prevents its proteolytic activation, blocking FOXO3 phosphorylation and nuclear translocation. J Biol Chem. 2007 Oct 19;282(42):30836-44. Epub 2007 Aug 28. PMID:17726016 doi:10.1074/jbc.M704542200
19. ↑ Han EK, Mcgonigal T, Butler C, Giranda VL, Luo Y. Characterization of Akt overexpression in MiaPaCa-2 cells: prohibitin is an Akt substrate both in vitro and in cells. Anticancer Res. 2008 Mar-Apr;28(2A):957-63. PMID:18507042
20. ↑ Jang SW, Liu X, Fu H, Rees H, Yepes M, Levey A, Ye K. Interaction of Akt-phosphorylated SRPK2 with 14-3-3 mediates cell cycle and cell death in neurons. J Biol Chem. 2009 Sep 4;284(36):24512-25. doi: 10.1074/jbc.M109.026237. Epub 2009, Jul 10. PMID:19592491 doi:10.1074/jbc.M109.026237
21. ↑ Bristow JM, Sellers MH, Majumdar D, Anderson B, Hu L, Webb DJ. The Rho-family GEF Asef2 activates Rac to modulate adhesion and actin dynamics and thereby regulate cell migration. J Cell Sci. 2009 Dec 15;122(Pt 24):4535-46. doi: 10.1242/jcs.053728. Epub 2009, Nov 24. PMID:19934221 doi:10.1242/jcs.053728
22. ↑ Romano D, Matallanas D, Weitsman G, Preisinger C, Ng T, Kolch W. Proapoptotic kinase MST2 coordinates signaling crosstalk between RASSF1A, Raf-1, and Akt. Cancer Res. 2010 Feb 1;70(3):1195-203. doi: 10.1158/0008-5472.CAN-09-3147. Epub, 2010 Jan 19. PMID:20086174 doi:10.1158/0008-5472.CAN-09-3147
23. ↑ Yuan Z, Kim D, Shu S, Wu J, Guo J, Xiao L, Kaneko S, Coppola D, Cheng JQ. Phosphoinositide 3-kinase/Akt inhibits MST1-mediated pro-apoptotic signaling through phosphorylation of threonine 120. J Biol Chem. 2010 Feb 5;285(6):3815-24. doi: 10.1074/jbc.M109.059675. Epub 2009, Nov 24. PMID:19940129 doi:10.1074/jbc.M109.059675
24. ↑ Nam SY, Seo HH, Park HS, An S, Kim JY, Yang KH, Kim CS, Jeong M, Jin YW. Phosphorylation of CLK2 at serine 34 and threonine 127 by AKT controls cell survival after ionizing radiation. J Biol Chem. 2010 Oct 8;285(41):31157-63. doi: 10.1074/jbc.M110.122044. Epub 2010, Aug 3. PMID:20682768 doi:10.1074/jbc.M110.122044
25. ↑ Chin YR, Toker A. The actin-bundling protein palladin is an Akt1-specific substrate that regulates breast cancer cell migration. Mol Cell. 2010 May 14;38(3):333-44. doi: 10.1016/j.molcel.2010.02.031. PMID:20471940 doi:10.1016/j.molcel.2010.02.031
26. ↑ Kim D, Shu S, Coppola MD, Kaneko S, Yuan ZQ, Cheng JQ. Regulation of proapoptotic mammalian ste20-like kinase MST2 by the IGF1-Akt pathway. PLoS One. 2010 Mar 9;5(3):e9616. doi: 10.1371/journal.pone.0009616. PMID:20231902 doi:10.1371/journal.pone.0009616
27. ↑ Mahajan K, Coppola D, Challa S, Fang B, Chen YA, Zhu W, Lopez AS, Koomen J, Engelman RW, Rivera C, Muraoka-Cook RS, Cheng JQ, Schonbrunn E, Sebti SM, Earp HS, Mahajan NP. Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PLoS One. 2010 Mar 19;5(3):e9646. doi: 10.1371/journal.pone.0009646. PMID:20333297 doi:10.1371/journal.pone.0009646
28. ↑ Coffer PJ, Woodgett JR. Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families. Eur J Biochem. 1991 Oct 15;201(2):475-81. PMID:1718748
29. ↑ Du K, Montminy M. CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem. 1998 Dec 4;273(49):32377-9. PMID:9829964
30. ↑ Walker KS, Deak M, Paterson A, Hudson K, Cohen P, Alessi DR. Activation of protein kinase B beta and gamma isoforms by insulin in vivo and by 3-phosphoinositide-dependent protein kinase-1 in vitro: comparison with protein kinase B alpha. Biochem J. 1998 Apr 1;331 ( Pt 1):299-308. PMID:9512493
31. ↑ Rena G, Guo S, Cichy SC, Unterman TG, Cohen P. Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. J Biol Chem. 1999 Jun 11;274(24):17179-83. PMID:10358075
32. ↑ Zimmermann S, Moelling K. Phosphorylation and regulation of Raf by Akt (protein kinase B). Science. 1999 Nov 26;286(5445):1741-4. PMID:10576742
33. ↑ Koh H, Lee KH, Kim D, Kim S, Kim JW, Chung J. Inhibition of Akt and its anti-apoptotic activities by tumor necrosis factor-induced protein kinase C-related kinase 2 (PRK2) cleavage. J Biol Chem. 2000 Nov 3;275(44):34451-8. PMID:10926925 doi:10.1074/jbc.M001753200
34. ↑ Kim AH, Khursigara G, Sun X, Franke TF, Chao MV. Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol. 2001 Feb;21(3):893-901. PMID:11154276 doi:10.1128/MCB.21.3.893-901.2001
35. ↑ Kane S, Sano H, Liu SC, Asara JM, Lane WS, Garner CC, Lienhard GE. A method to identify serine kinase substrates. Akt phosphorylates a novel adipocyte protein with a Rab GTPase-activating protein (GAP) domain. J Biol Chem. 2002 Jun 21;277(25):22115-8. Epub 2002 May 6. PMID:11994271 doi:10.1074/jbc.C200198200
36. ↑ Fujita N, Sato S, Katayama K, Tsuruo T. Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization. J Biol Chem. 2002 Aug 9;277(32):28706-13. Epub 2002 May 31. PMID:12042314 doi:10.1074/jbc.M203668200
37. ↑ Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell. 2002 Jul;10(1):151-62. PMID:12150915
38. ↑ Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J, Arteaga CL. PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat Med. 2002 Oct;8(10):1145-52. Epub 2002 Sep 16. PMID:12244301 doi:10.1038/nm759
39. ↑ Lennartsson J, Wernstedt C, Engstrom U, Hellman U, Ronnstrand L. Identification of Tyr900 in the kinase domain of c-Kit as a Src-dependent phosphorylation site mediating interaction with c-Crk. Exp Cell Res. 2003 Aug 1;288(1):110-8. PMID:12878163
40. ↑ Enomoto A, Murakami H, Asai N, Morone N, Watanabe T, Kawai K, Murakumo Y, Usukura J, Kaibuchi K, Takahashi M. Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev Cell. 2005 Sep;9(3):389-402. PMID:16139227 doi:S1534-5807(05)00295-9
41. ↑ Srinivas H, Xia D, Moore NL, Uray IP, Kim H, Ma L, Weigel NL, Brown PH, Kurie JM. Akt phosphorylates and suppresses the transactivation of retinoic acid receptor alpha. Biochem J. 2006 May 1;395(3):653-62. PMID:16417524 doi:10.1042/BJ20051794
42. ↑ Heron-Milhavet L, Franckhauser C, Rana V, Berthenet C, Fisher D, Hemmings BA, Fernandez A, Lamb NJ. Only Akt1 is required for proliferation, while Akt2 promotes cell cycle exit through p21 binding. Mol Cell Biol. 2006 Nov;26(22):8267-80. Epub 2006 Sep 18. PMID:16982699 doi:10.1128/MCB.00201-06
43. ↑ Jang SW, Yang SJ, Srinivasan S, Ye K. Akt phosphorylates MstI and prevents its proteolytic activation, blocking FOXO3 phosphorylation and nuclear translocation. J Biol Chem. 2007 Oct 19;282(42):30836-44. Epub 2007 Aug 28. PMID:17726016 doi:10.1074/jbc.M704542200
44. ↑ Han EK, Mcgonigal T, Butler C, Giranda VL, Luo Y. Characterization of Akt overexpression in MiaPaCa-2 cells: prohibitin is an Akt substrate both in vitro and in cells. Anticancer Res. 2008 Mar-Apr;28(2A):957-63. PMID:18507042
45. ↑ Jang SW, Liu X, Fu H, Rees H, Yepes M, Levey A, Ye K. Interaction of Akt-phosphorylated SRPK2 with 14-3-3 mediates cell cycle and cell death in neurons. J Biol Chem. 2009 Sep 4;284(36):24512-25. doi: 10.1074/jbc.M109.026237. Epub 2009, Jul 10. PMID:19592491 doi:10.1074/jbc.M109.026237
46. ↑ Bristow JM, Sellers MH, Majumdar D, Anderson B, Hu L, Webb DJ. The Rho-family GEF Asef2 activates Rac to modulate adhesion and actin dynamics and thereby regulate cell migration. J Cell Sci. 2009 Dec 15;122(Pt 24):4535-46. doi: 10.1242/jcs.053728. Epub 2009, Nov 24. PMID:19934221 doi:10.1242/jcs.053728
47. ↑ Romano D, Matallanas D, Weitsman G, Preisinger C, Ng T, Kolch W. Proapoptotic kinase MST2 coordinates signaling crosstalk between RASSF1A, Raf-1, and Akt. Cancer Res. 2010 Feb 1;70(3):1195-203. doi: 10.1158/0008-5472.CAN-09-3147. Epub, 2010 Jan 19. PMID:20086174 doi:10.1158/0008-5472.CAN-09-3147
48. ↑ Yuan Z, Kim D, Shu S, Wu J, Guo J, Xiao L, Kaneko S, Coppola D, Cheng JQ. Phosphoinositide 3-kinase/Akt inhibits MST1-mediated pro-apoptotic signaling through phosphorylation of threonine 120. J Biol Chem. 2010 Feb 5;285(6):3815-24. doi: 10.1074/jbc.M109.059675. Epub 2009, Nov 24. PMID:19940129 doi:10.1074/jbc.M109.059675
49. ↑ Nam SY, Seo HH, Park HS, An S, Kim JY, Yang KH, Kim CS, Jeong M, Jin YW. Phosphorylation of CLK2 at serine 34 and threonine 127 by AKT controls cell survival after ionizing radiation. J Biol Chem. 2010 Oct 8;285(41):31157-63. doi: 10.1074/jbc.M110.122044. Epub 2010, Aug 3. PMID:20682768 doi:10.1074/jbc.M110.122044
50. ↑ Chin YR, Toker A. The actin-bundling protein palladin is an Akt1-specific substrate that regulates breast cancer cell migration. Mol Cell. 2010 May 14;38(3):333-44. doi: 10.1016/j.molcel.2010.02.031. PMID:20471940 doi:10.1016/j.molcel.2010.02.031
51. ↑ Kim D, Shu S, Coppola MD, Kaneko S, Yuan ZQ, Cheng JQ. Regulation of proapoptotic mammalian ste20-like kinase MST2 by the IGF1-Akt pathway. PLoS One. 2010 Mar 9;5(3):e9616. doi: 10.1371/journal.pone.0009616. PMID:20231902 doi:10.1371/journal.pone.0009616
52. ↑ Mahajan K, Coppola D, Challa S, Fang B, Chen YA, Zhu W, Lopez AS, Koomen J, Engelman RW, Rivera C, Muraoka-Cook RS, Cheng JQ, Schonbrunn E, Sebti SM, Earp HS, Mahajan NP. Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PLoS One. 2010 Mar 19;5(3):e9646. doi: 10.1371/journal.pone.0009646. PMID:20333297 doi:10.1371/journal.pone.0009646
53. ↑ Boyle WJ, Smeal T, Defize LH, Angel P, Woodgett JR, Karin M, Hunter T. Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. Cell. 1991 Feb 8;64(3):573-84. PMID:1846781
54. ↑ Welsh GI, Proud CG. Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. Biochem J. 1993 Sep 15;294 ( Pt 3):625-9. PMID:8397507
55. ↑ Beals CR, Sheridan CM, Turck CW, Gardner P, Crabtree GR. Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science. 1997 Mar 28;275(5308):1930-4. PMID:9072970
56. ↑ Li Y, Bharti A, Chen D, Gong J, Kufe D. Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin. Mol Cell Biol. 1998 Dec;18(12):7216-24. PMID:9819408
57. ↑ Frame S, Cohen P, Biondi RM. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol Cell. 2001 Jun;7(6):1321-7. PMID:11430833
58. ↑ Cho JH, Johnson GV. Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3beta (GSK3beta) plays a critical role in regulating tau's ability to bind and stabilize microtubules. J Neurochem. 2004 Jan;88(2):349-58. PMID:14690523
59. ↑ Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol. 2004 Oct;6(10):931-40. Epub 2004 Sep 26. PMID:15448698 doi:10.1038/ncb1173
60. ↑ Hashimoto YK, Satoh T, Okamoto M, Takemori H. Importance of autophosphorylation at Ser186 in the A-loop of salt inducible kinase 1 for its sustained kinase activity. J Cell Biochem. 2008 Aug 1;104(5):1724-39. doi: 10.1002/jcb.21737. PMID:18348280 doi:10.1002/jcb.21737
61. ↑ Heyd F, Lynch KW. Phosphorylation-dependent regulation of PSF by GSK3 controls CD45 alternative splicing. Mol Cell. 2010 Oct 8;40(1):126-37. doi: 10.1016/j.molcel.2010.09.013. PMID:20932480 doi:10.1016/j.molcel.2010.09.013
62. ↑ Zaoui K, Benseddik K, Daou P, Salaun D, Badache A. ErbB2 receptor controls microtubule capture by recruiting ACF7 to the plasma membrane of migrating cells. Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18517-22. doi:, 10.1073/pnas.1000975107. Epub 2010 Oct 11. PMID:20937854 doi:10.1073/pnas.1000975107
63. ↑ Sun L, Lv F, Guo X, Gao G. Glycogen synthase kinase 3beta (GSK3beta) modulates antiviral activity of zinc-finger antiviral protein (ZAP). J Biol Chem. 2012 Jun 29;287(27):22882-8. doi: 10.1074/jbc.M111.306373. Epub 2012, Apr 18. PMID:22514281 doi:10.1074/jbc.M111.306373
64. ↑ Dajani R, Fraser E, Roe SM, Yeo M, Good VM, Thompson V, Dale TC, Pearl LH. Structural basis for recruitment of glycogen synthase kinase 3beta to the axin-APC scaffold complex. EMBO J. 2003 Feb 3;22(3):494-501. PMID:12554650 doi:10.1093/emboj/cdg068
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