1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Pharmacology and Toxicology
  4. Volume 61, 2021
  5. Article

Annual Review of Pharmacology and Toxicology

Volume 61, 2021

Drugs That Regulate Local Cell Signaling: AKAP Targeting as a Therapeutic Option

Abstract

Cells respond to environmental cues by mobilizing signal transduction cascades that engage protein kinases and phosphoprotein phosphatases. Correct organization of these enzymes in space and time enables the efficient and precise transmission of chemical signals. The cyclic AMP-dependent protein kinase A is compartmentalized through its association with A-kinase anchoring proteins (AKAPs). AKAPs are a family of multivalent scaffolds that constrain signaling enzymes and effectors at subcellular locations to drive essential physiological events. More recently, it has been recognized that defective signaling in certain endocrine disorders and cancers proceeds through pathological AKAP complexes. Consequently, pharmacologically targeting these macromolecular complexes unlocks new therapeutic opportunities for a growing number of clinical indications. This review highlights recent findings on AKAP signaling in disease, particularly in certain cancers, and offers an overview of peptides and small molecules that locally regulate AKAP-binding partners.

Keyword(s): A-kinase anchoring protein, anchoring disruptor agents, precision pharmacology, protein kinase A, small-molecule inhibitors, spatial signaling
Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-022420-112134
2021-01-06
2024-04-27
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/61/1/annurev-pharmtox-022420-112134.html?itemId=/content/journals/10.1146/annurev-pharmtox-022420-112134&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Sutherland EW. 1972. Studies on the mechanism of hormone action. Science 171:401–8
     [Google Scholar]
  2. 2. 
    Scott JD, Pawson T. 2009. Cell signaling in space and time: where proteins come together and when they're apart. Science 326:1220–24
     [Google Scholar]
  3. 3. 
    Wong W, Scott JD. 2004. AKAP signalling complexes: focal points in space and time. Nat. Rev. Mol. Cell Biol. 5:959–71
     [Google Scholar]
  4. 4. 
    Tasken K, Aandahl EM. 2004. Localized effects of cAMP mediated by distinct routes of protein kinase A. Physiol. Rev. 84:137–67
     [Google Scholar]
  5. 5. 
    Scott JD, Dessauer CW, Tasken K 2013. Creating order from chaos: cellular regulation by kinase anchoring. Annu. Rev. Pharmacol. Toxicol. 53:187–210
     [Google Scholar]
  6. 6. 
    Langeberg LK, Scott JD. 2015. Signalling scaffolds and local organization of cellular behaviour. Nat. Rev. Mol. Cell Biol. 16:232–44
     [Google Scholar]
  7. 7. 
    Taylor SS, Ilouz R, Zhang P, Kornev AP 2012. Assembly of allosteric macromolecular switches: lessons from PKA. Nat. Rev. Mol. Cell Biol. 13:646–58
     [Google Scholar]
  8. 8. 
    Corbin JD, Keely SL, Park CR 1975. The distribution and dissociation of cyclic adenosine 3′:5′-monophosphate-dependent protein kinase in adipose, cardiac, and other tissues. J. Biol. Chem. 250:218–25
     [Google Scholar]
  9. 9. 
    Potter RL, Stafford PH, Taylor S 1978. Regulatory subunit of cyclic AMP-dependent protein kinase I from porcine skeletal muscle: purification and proteolysis. Arch. Biochem. Biophys. 190:174–80
     [Google Scholar]
  10. 10. 
    Isensee J, Kaufholz M, Knape MJ, Hasenauer J, Hammerich H et al. 2018. PKA-RII subunit phosphorylation precedes activation by cAMP and regulates activity termination. J. Cell Biol. 217:62167–84
     [Google Scholar]
  11. 11. 
    Potter RL, Taylor SS. 1979. Relationships between structural domains and function in the regulatory subunit of cAMP-dependent protein kinases I and II from porcine skeletal muscle. J. Biol. Chem. 254:2413–18
     [Google Scholar]
  12. 12. 
    Smith FD, Esseltine JL, Nygren PJ, Veesler D, Byrne DP et al. 2017. Local protein kinase A action proceeds through intact holoenzymes. Science 356:1288–93
     [Google Scholar]
  13. 13. 
    Gabrovsek L, Bucko P, Carnegie GK, Scott JD 2017. A-kinase anchoring protein (AKAP). Encyclopedia of Signaling Molecules S Choi New York: Springer https://doi.org/10.1007/978-3-319-67199-4_218
     [Crossref] [Google Scholar]
  14. 14. 
    Carr DW, Bishop SE, Acott TS, Scott JD 1991. The tissue distribution of RI and RII-anchoring proteins. FASEB J 5:A1529
     [Google Scholar]
  15. 15. 
    Newlon MG, Roy M, Hausken ZE, Scott JD, Jennings PA 1997. The A-kinase anchoring domain of type IIa cAMP-dependent protein kinase is highly helical. J. Biol. Chem. 272:23637–44
     [Google Scholar]
  16. 16. 
    Smith FD, Reichow SL, Esseltine JL, Shi D, Langeberg LK et al. 2013. Intrinsic disorder within an AKAP-protein kinase A complex guides local substrate phosphorylation. eLife 2:e01319
     [Google Scholar]
  17. 17. 
    Carr DW, Hausken ZE, Fraser ID, Stofko-Hahn RE, Scott JD 1992. Association of the type II cAMP-dependent protein kinase with a human thyroid RII-anchoring protein: cloning and characterization of the RII-binding domain. J. Biol. Chem. 267:13376–82
     [Google Scholar]
  18. 18. 
    Theurkauf WE, Vallee RB. 1982. Molecular characterization of the cAMP-dependent protein kinase bound to microtubule-associated protein 2. J. Biol. Chem. 257:3284–90
     [Google Scholar]
  19. 19. 
    Huang LJ, Durick K, Weiner JA, Chun J, Taylor SS 1997. Identification of a novel dual specificity protein kinase A anchoring protein, D-AKAP1. J. Biol. Chem. 272:8057–64
     [Google Scholar]
  20. 20. 
    Kovanich D, van der Heyden MA, Aye TT, van Veen TA, Heck AJ, Scholten A 2010. Sphingosine kinase interacting protein is an A-kinase anchoring protein specific for type I cAMP-dependent protein kinase. Chembiochem 11:963–71
     [Google Scholar]
  21. 21. 
    Means CK, Lygren B, Langeberg LK, Jain A, Dixon RE et al. 2011. An entirely specific type I A-kinase anchoring protein that can sequester two molecules of protein kinase A at mitochondria. PNAS 108:E1227–35
     [Google Scholar]
  22. 22. 
    Esseltine JL, Scott JD. 2013. AKAP signaling complexes: pointing towards the next generation of therapeutic targets. ? Trends Pharmacol. Sci. 34:648–55
     [Google Scholar]
  23. 23. 
    Smith FD, Omar MH, Nygren PJ, Soughayer J, Hoshi N et al. 2018. Single nucleotide polymorphisms alter kinase anchoring and the subcellular targeting of A-kinase anchoring proteins. PNAS 115:E11465–74
     [Google Scholar]
  24. 24. 
    Dessauer CW. 2009. Adenylyl cyclase–A-kinase anchoring protein complexes: the next dimension in cAMP signaling. Mol. Pharmacol. 76:935–41
     [Google Scholar]
  25. 25. 
    Lomas O, Zaccolo M. 2014. Phosphodiesterases maintain signaling fidelity via compartmentalization of cyclic nucleotides. Physiology 29:141–49
     [Google Scholar]
  26. 26. 
    Zaccolo M, De Giorgi F, Cho CY, Feng L, Knapp T et al. 2000. A genetically encoded, fluorescent indicator for cyclic AMP in living cells. Nat. Cell Biol. 2:25–29
     [Google Scholar]
  27. 27. 
    Schleicher K, Zaccolo M. 2018. Using cAMP sensors to study cardiac nanodomains. J. Cardiovasc. Dev. Dis. 5:e17
     [Google Scholar]
  28. 28. 
    Gold MG, Reichow SL, O'Neill SE, Weisbrod CR, Langeberg LK et al. 2012. AKAP2 anchors PKA with aquaporin-0 to support ocular lens transparency. EMBO Mol. Med. 4:15–26
     [Google Scholar]
  29. 29. 
    Suryavanshi SV, Jadhav SM, McConnell BK 2018. Polymorphisms/mutations in A-kinase anchoring proteins (AKAPs): role in the cardiovascular system. J. Cardiovasc. Dev. Dis. 5:e7
     [Google Scholar]
  30. 30. 
    Wild AR, Dell'Acqua ML. 2018. Potential for therapeutic targeting of AKAP signaling complexes in nervous system disorders. Pharmacol. Ther. 185:99–121
     [Google Scholar]
  31. 31. 
    Carr DW, Stofko-Hahn RE, Fraser IDC, Cone RD, Scott JD 1992. Localization of the cAMP-dependent protein kinase to the postsynaptic densities by A-kinase anchoring proteins: characterization of AKAP79. J. Biol. Chem. 24:16816–23
     [Google Scholar]
  32. 32. 
    Klauck TM, Faux MC, Labudda K, Langeberg LK, Jaken S, Scott JD 1996. Coordination of three signaling enzymes by AKAP79, a mammalian scaffold protein. Science 271:1589–92
     [Google Scholar]
  33. 33. 
    Tunquist BJ, Hoshi N, Guire ES, Zhang F, Mullendorff K et al. 2008. Loss of AKAP150 perturbs distinct neuronal processes in mice. PNAS 105:12557–62
     [Google Scholar]
  34. 34. 
    Sanderson JL, Gorski JA, Gibson ES, Lam P, Freund RK et al. 2012. AKAP150-anchored calcineurin regulates synaptic plasticity by limiting synaptic incorporation of Ca2+-permeable AMPA receptors. J. Neurosci. 32:15036–52
     [Google Scholar]
  35. 35. 
    Colledge M, Dean RA, Scott GK, Langeberg LK, Huganir RL, Scott JD 2000. Targeting of PKA to glutamate receptors through a MAGUK-AKAP complex. Neuron 27:107–19
     [Google Scholar]
  36. 36. 
    Diering GH, Gustina AS, Huganir RL 2014. PKA-GluA1 coupling via AKAP5 controls AMPA receptor phosphorylation and cell-surface targeting during bidirectional homeostatic plasticity. Neuron 84:790–805
     [Google Scholar]
  37. 37. 
    Sanderson JL, Gorski JA, Dell'Acqua ML 2016. NMDA receptor-dependent LTD requires transient synaptic incorporation of Ca2+-permeable AMPARs mediated by AKAP150-anchored PKA and calcineurin. Neuron 89:1000–15
     [Google Scholar]
  38. 38. 
    Summers KC, Bogard AS, Tavalin SJ 2019. Preferential generation of Ca2+-permeable AMPA receptors by AKAP79-anchored protein kinase C proceeds via GluA1 subunit phosphorylation at Ser-831. J. Biol. Chem. 294:5521–35
     [Google Scholar]
  39. 39. 
    Zhang J, Carver CM, Choveau FS, Shapiro MS 2016. Clustering and functional coupling of diverse ion channels and signaling proteins revealed by super-resolution STORM microscopy in neurons. Neuron 92:461–78
     [Google Scholar]
  40. 40. 
    Hoshi N, Langeberg LK, Scott JD 2005. Distinct enzyme combinations in AKAP signalling complexes permit functional diversity. Nat. Cell Biol. 7:1066–73
     [Google Scholar]
  41. 41. 
    Zhang J, Bal M, Bierbower S, Zaika O, Shapiro MS 2011. AKAP79/150 signal complexes in G-protein modulation of neuronal ion channels. J. Neurosci. 31:7199–211
     [Google Scholar]
  42. 42. 
    Dittmer PJ, Dell'Acqua ML, Sather WA 2014. Ca2+/calcineurin-dependent inactivation of neuronal L-type Ca2+ channels requires priming by AKAP-anchored protein kinase A. Cell Rep 7:1410–16
     [Google Scholar]
  43. 43. 
    Murphy JG, Crosby KC, Dittmer PJ, Sather WA, Dell'Acqua ML 2019. AKAP79/150 recruits the transcription factor NFAT to regulate signaling to the nucleus by neuronal L-type Ca2+ channels. Mol. Biol. Cell 30:1743–56
     [Google Scholar]
  44. 44. 
    Nystoriak MA, Nieves-Cintron M, Nygren PJ, Hinke SA, Nichols CB et al. 2014. AKAP150 contributes to enhanced vascular tone by facilitating large-conductance Ca2+-activated K+ channel remodeling in hyperglycemia and diabetes mellitus. Circ. Res. 114:607–15
     [Google Scholar]
  45. 45. 
    Nieves-Cintron M, Hirenallur-Shanthappa D, Nygren PJ, Hinke SA, Dell'Acqua ML et al. 2016. AKAP150 participates in calcineurin/NFAT activation during the down-regulation of voltage-gated K+ currents in ventricular myocytes following myocardial infarction. Cell Signal 28:733–40
     [Google Scholar]
  46. 46. 
    Navedo MF, Cheng EP, Yuan C, Votaw S, Molkentin JD et al. 2010. Increased coupled gating of L-type Ca2+ channels during hypertension and Timothy syndrome. Circ. Res. 106:748–56
     [Google Scholar]
  47. 47. 
    Lester LB, Faux MC, Nauert JB, Scott JD 2001. Targeted protein kinase A and PP-2B regulate insulin secretion through reversible phosphorylation. Endocrinology 142:1218–27
     [Google Scholar]
  48. 48. 
    Hinke SA, Navedo MF, Ulman A, Whiting JL, Nygren PJ et al. 2012. Anchored phosphatases modulate glucose homeostasis. EMBO J 31:3991–4004
     [Google Scholar]
  49. 49. 
    Nygren PJ, Mehta S, Schweppe DK, Langeberg LK, Whiting JL et al. 2017. Intrinsic disorder within AKAP79 fine-tunes anchored phosphatase activity toward substrates and drug sensitivity. eLife 6:e30872
     [Google Scholar]
  50. 50. 
    Schillace RV, Voltz JW, Sim AT, Shenolikar S, Scott JD 2001. Multiple interactions within the AKAP220 signaling complex contribute to protein phosphatase 1 regulation. J. Biol. Chem. 276:12128–34
     [Google Scholar]
  51. 51. 
    Logue JS, Whiting JL, Tunquist B, Langeberg LK, Scott JD 2011. Anchored protein kinase A recruitment of active Rac GTPase. J. Biol. Chem. 286:22113–21
     [Google Scholar]
  52. 52. 
    Whiting JL, Nygren PJ, Tunquist BJ, Langeberg LK, Seternes OM, Scott JD 2015. Protein kinase A opposes the phosphorylation-dependent recruitment of glycogen synthase kinase 3β to A-kinase anchoring protein 220. J. Biol. Chem. 290:19445–57
     [Google Scholar]
  53. 53. 
    Logue JS, Whiting JL, Tunquist B, Sacks DB, Langeberg LK et al. 2011. AKAP220 protein organizes signaling elements that impact cell migration. J. Biol. Chem. 286:39269–81
     [Google Scholar]
  54. 54. 
    Okutsu R, Rai T, Kikuchi A, Ohno M, Uchida K et al. 2008. AKAP220 colocalizes with AQP2 in the inner medullary collecting ducts. Kidney Int 74:1429–33
     [Google Scholar]
  55. 55. 
    Whiting JL, Ogier L, Forbush KA, Bucko P, Gopalan J et al. 2016. AKAP220 manages apical actin networks that coordinate aquaporin-2 location and renal water reabsorption. PNAS 113:E4328–37
     [Google Scholar]
  56. 56. 
    Stork PJ, Schmitt JM. 2002. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol 12:258–66
     [Google Scholar]
  57. 57. 
    Pattabiraman DR, Bierie B, Kober KI, Thiru P, Krall JA et al. 2016. Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability. Science 351:aad3680
     [Google Scholar]
  58. 58. 
    Beuschlein F, Fassnacht M, Assie G, Calebiro D, Stratakis CA et al. 2014. Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome. N. Engl. J. Med. 370:1019–28
     [Google Scholar]
  59. 59. 
    Cao Y, He M, Gao Z, Peng Y, Li Y et al. 2014. Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome. Science 344:913–17
     [Google Scholar]
  60. 60. 
    Sato Y, Maekawa S, Ishii R, Sanada M, Morikawa T et al. 2014. Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome. Science 344:917–20
     [Google Scholar]
  61. 61. 
    Goh G, Scholl UI, Healy JM, Choi M, Prasad ML et al. 2014. Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors. Nat. Genet. 46:613–17
     [Google Scholar]
  62. 62. 
    Riggle KM, Riehle KJ, Kenerson HL, Turnham R, Homma MK et al. 2016. Enhanced cAMP-stimulated protein kinase A activity in human fibrolamellar hepatocellular carcinoma. Pediatr. Res. 80:110–18
     [Google Scholar]
  63. 63. 
    Honeyman JN, Simon EP, Robine N, Chiaroni-Clarke R, Darcy DG et al. 2014. Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science 343:1010–14
     [Google Scholar]
  64. 64. 
    Turnham RE, Smith FD, Kenerson HL, Omar MH, Golkowski M et al. 2019. An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma. eLife 8:e44187
     [Google Scholar]
  65. 65. 
    Ciampi R, Knauf JA, Kerler R, Gandhi M, Zhu Z et al. 2005. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J. Clin. Investig. 115:94–101
     [Google Scholar]
  66. 66. 
    Kjallquist U, Erlandsson R, Tobin NP, Alkodsi A, Ullah I et al. 2018. Exome sequencing of primary breast cancers with paired metastatic lesions reveals metastasis-enriched mutations in the A-kinase anchoring protein family (AKAPs). BMC Cancer 18:174
     [Google Scholar]
  67. 67. 
    Hu X, Harvey SE, Zheng R, Lyu J, Grzeskowiak CL et al. 2020. The RNA-binding protein AKAP8 suppresses tumor metastasis by antagonizing EMT-associated alternative splicing. Nat. Commun. 11:486
     [Google Scholar]
  68. 68. 
    Coghlan VM, Langeberg LK, Fernandez A, Lamb NJC, Scott JD 1994. Cloning and characterization of AKAP95, a nuclear protein that associates with the regulatory subunit of type II cAMP-dependent protein kinase. J. Biol. Chem. 269:7658–65
     [Google Scholar]
  69. 69. 
    Eide T, Coghlan V, Orstavik S, Holsve C, Solberg R et al. 1998. Molecular cloning, chromosomal localization, and cell cycle-dependent subcellular distribution of the A-kinase anchoring protein, AKAP95. Exp. Cell Res. 238:305–16
     [Google Scholar]
  70. 70. 
    Zhang M, Zhao Y, Zhao J, Huang T, Wu Y 2019. Impact of AKAP6 polymorphisms on glioma susceptibility and prognosis. BMC Neurol 19:296
     [Google Scholar]
  71. 71. 
    Kapiloff MS, Schillace RV, Westphal AM, Scott JD 1999. mAKAP: an A-kinase anchoring protein targeted to the nuclear membrane of differentiated myocytes. J. Cell Sci. 112:2725–36
     [Google Scholar]
  72. 72. 
    Diviani D, Dodge-Kafka KL, Li J, Kapiloff MS 2011. A-kinase anchoring proteins: scaffolding proteins in the heart. Am. J. Physiol. Heart Circ. Physiol. 301:H1742–53
     [Google Scholar]
  73. 73. 
    Michel JJ, Townley IK, Dodge-Kafka KL, Zhang F, Kapiloff MS, Scott JD 2005. Spatial restriction of PDK1 activation cascades by anchoring to mAKAPα. Mol. Cell 20:661–72
     [Google Scholar]
  74. 74. 
    Gordon T, Grove B, Loftus JC, O'Toole T, McMillan R et al. 1992. Molecular cloning and preliminary characterization of a novel cytoplasmic antigen recognized by myasthenia gravis sera. J. Clin. Investig. 90:992–99
     [Google Scholar]
  75. 75. 
    Nauert JB, Klauck TM, Langeberg LK, Scott JD 1997. Gravin, an autoantigen recognized by serum from myasthenia gravis patients, is a kinase scaffold protein. Curr. Biol. 7:52–62
     [Google Scholar]
  76. 76. 
    Gelman IH. 2010. Emerging roles for SSeCKS/Gravin/AKAP12 in the control of cell proliferation, cancer malignancy, and barriergenesis. Genes Cancer 1:1147–56
     [Google Scholar]
  77. 77. 
    Muramatsu M, Gao L, Peresie J, Balderman B, Akakura S, Gelman IH 2017. SSeCKS/AKAP12 scaffolding functions suppress B16F10-induced peritoneal metastasis by attenuating CXCL9/10 secretion by resident fibroblasts. Oncotarget 8:70281–98
     [Google Scholar]
  78. 78. 
    Gelman IH. 2012. Suppression of tumor and metastasis progression through the scaffolding functions of SSeCKS/Gravin/AKAP12. Cancer Metastasis Rev 31:493–500
     [Google Scholar]
  79. 79. 
    Bateman NW, Jaworski E, Ao W, Wang G, Litzi T et al. 2015. Elevated AKAP12 in paclitaxel-resistant serous ovarian cancer cells is prognostic and predictive of poor survival in patients. J. Proteome Res. 14:1900–10
     [Google Scholar]
  80. 80. 
    Wilhelm T, Lipka DB, Witte T, Wierzbinska JA, Fluhr S et al. 2016. Epigenetic silencing of AKAP12 in juvenile myelomonocytic leukemia. Epigenetics 11:110–19
     [Google Scholar]
  81. 81. 
    Parada CA, Osbun J, Kaur S, Yakkioui Y, Shi M et al. 2018. Kinome and phosphoproteome of high-grade meningiomas reveal AKAP12 as a central regulator of aggressiveness and its possible role in progression. Sci. Rep. 8:2098
     [Google Scholar]
  82. 82. 
    Su B, Bu Y, Engelberg D, Gelman IH 2010. SSeCKS/Gravin/AKAP12 inhibits cancer cell invasiveness and chemotaxis by suppressing a protein kinase C-Raf/MEK/ERK pathway. J. Biol. Chem. 285:4578–86
     [Google Scholar]
  83. 83. 
    Akakura S, Nochajski P, Gao L, Sotomayor P, Matsui S, Gelman IH 2010. Rb-dependent cellular senescence, multinucleation and susceptibility to oncogenic transformation through PKC scaffolding by SSeCKS/AKAP12. Cell Cycle 9:4656–65
     [Google Scholar]
  84. 84. 
    Newton AC, Brognard J. 2017. Reversing the paradigm: protein kinase C as a tumor suppressor. Trends Pharmacol. Sci. 38:438–47
     [Google Scholar]
  85. 85. 
    Hehnly H, Canton D, Bucko P, Langeberg LK, Ogier L et al. 2015. A mitotic kinase scaffold depleted in testicular seminomas impacts spindle orientation in germ line stem cells. eLife 4:e09384
     [Google Scholar]
  86. 86. 
    Canton DA, Keene CD, Swinney K, Langeberg LK, Nguyen V et al. 2012. Gravin is a transitory effector of Polo-like kinase 1 during cell division. Mol. Cell 48:547–59
     [Google Scholar]
  87. 87. 
    Colicino EG, Garrastegui AM, Freshour J, Santra P, Post DE et al. 2018. Gravin regulates centrosome function through PLK1. Mol. Biol. Cell 29:532–41
     [Google Scholar]
  88. 88. 
    Bucko PJ, Lombard CK, Rathbun L, Garcia I, Bhat A et al. 2019. Subcellular drug targeting illuminates local kinase action. eLife 8:e52220
     [Google Scholar]
  89. 89. 
    Paulucci-Holthauzen AA, Vergara LA, Bellot LJ, Canton D, Scott JD, O'Connor KL 2009. Spatial distribution of protein kinase A activity during cell migration is mediated by A-kinase anchoring protein AKAP Lbc. J. Biol. Chem. 284:5956–67
     [Google Scholar]
  90. 90. 
    Smith FD, Langeberg LK, Cellurale C, Pawson T, Morrison DK et al. 2010. AKAP-Lbc enhances cyclic AMP control of the ERK1/2 cascade. Nat. Cell Biol. 12:1242–49
     [Google Scholar]
  91. 91. 
    Ohgushi M, Minaguchi M, Sasai Y 2015. Rho-signaling-directed YAP/TAZ activity underlies the long-term survival and expansion of human embryonic stem cells. Cell Stem Cell 17:448–61
     [Google Scholar]
  92. 92. 
    Diviani D, Soderling J, Scott JD 2001. AKAP-Lbc anchors protein kinase A and nucleates Gα12-selective Rho-mediated stress fiber formation. J. Biol. Chem. 276:44247–57
     [Google Scholar]
  93. 93. 
    Klussmann E, Edemir B, Pepperle B, Tamma G, Henn V et al. 2001. Ht31: the first protein kinase A anchoring protein to integrate protein kinase A and Rho signaling. FEBS Lett 507:264–68
     [Google Scholar]
  94. 94. 
    Diviani D, Osman H, Reggi E 2018. A-kinase anchoring protein-Lbc: a molecular scaffold involved in cardiac protection. J. Cardiovasc. Dev. Dis. 5:e12
     [Google Scholar]
  95. 95. 
    Lin RY, Moss SB, Rubin CS 1995. Characterization of S-AKAP84, a novel developmentally regulated A kinase anchor protein of male germ cells. J. Biol. Chem. 270:27804–11
     [Google Scholar]
  96. 96. 
    Aggarwal S, Gabrovsek L, Langeberg LK, Golkowski M, Ong SE et al. 2019. Depletion of dAKAP1-protein kinase A signaling islands from the outer mitochondrial membrane alters breast cancer cell metabolism and motility. J. Biol. Chem. 294:3152–68
     [Google Scholar]
  97. 97. 
    Steen RL, Martins SB, Tasken K, Collas P 2000. Recruitment of protein phosphatase 1 to the nuclear envelope by A-kinase anchoring protein AKAP149 is a prerequisite for nuclear lamina assembly. J. Cell Biol. 150:1251–62
     [Google Scholar]
  98. 98. 
    Meiri D, Greeve MA, Brunet A, Finan D, Wells CD et al. 2009. Modulation of Rho guanine exchange factor Lfc activity by protein kinase A-mediated phosphorylation. Mol. Cell. Biol. 29:5963–73
     [Google Scholar]
  99. 99. 
    Rinaldi L, Sepe M, Delle Donne R, Conte K, Arcella A et al. 2017. Mitochondrial AKAP1 supports mTOR pathway and tumor growth. Cell Death Dis 8:e2842
     [Google Scholar]
  100. 100. 
    Troger J, Moutty MC, Skroblin P, Klussmann E 2012. A-kinase anchoring proteins as potential drug targets. Br. J. Pharmacol. 166:420–33
     [Google Scholar]
  101. 101. 
    Calejo AI, Tasken K. 2015. Targeting protein-protein interactions in complexes organized by A kinase anchoring proteins. Front. Pharmacol. 6:192
     [Google Scholar]
  102. 102. 
    Kennedy EJ, Scott JD. 2015. Selective disruption of the AKAP signaling complexes. Methods Mol. Biol. 1294:137–50
     [Google Scholar]
  103. 103. 
    Deak VA, Klussmann E. 2016. Pharmacological interference with protein-protein interactions of A-kinase anchoring proteins as a strategy for the treatment of disease. Curr. Drug Targets 17:1147–71
     [Google Scholar]
  104. 104. 
    Carr DW, Scott JD. 1992. Blotting and band-shifting: Techniques for studying protein-protein interactions. Trends Biochem. Sci. 17:246–49
     [Google Scholar]
  105. 105. 
    Rosenmund C, Carr DW, Bergeson SE, Nilaver G, Scott JD, Westbrook GL 1994. Anchoring of protein kinase A is required for modulation of AMPA/kainate receptors on hippocampal neurons. Nature 368:853–56
     [Google Scholar]
  106. 106. 
    Dukic AR, Haugen LH, Pidoux G, Leithe E, Bakke O, Tasken K 2017. A protein kinase A-ezrin complex regulates connexin 43 gap junction communication in liver epithelial cells. Cell Signal 32:1–11
     [Google Scholar]
  107. 107. 
    Ma L, Dong F, Denis M, Feng Y, Wang MD, Zha X 2011. Ht31, a protein kinase A anchoring inhibitor, induces robust cholesterol efflux and reverses macrophage foam cell formation through ATP-binding cassette transporter A1. J. Biol. Chem. 286:3370–78
     [Google Scholar]
  108. 108. 
    Thakkar A, Aljameeli A, Thomas S, Shah GV 2016. A-kinase anchoring protein 2 is required for calcitonin-mediated invasion of cancer cells. Endocr. Relat. Cancer 23:1–14
     [Google Scholar]
  109. 109. 
    Wang Y, Ho TG, Bertinetti D, Neddermann M, Franz E et al. 2014. Isoform-selective disruption of AKAP-localized PKA using hydrocarbon stapled peptides. ACS Chem. Biol. 9:635–42
     [Google Scholar]
  110. 110. 
    Wang Y, Ho TG, Franz E, Hermann JS, Smith FD et al. 2015. PKA-type I selective constrained peptide disruptors of AKAP complexes. ACS Chem. Biol. 10:1502–10
     [Google Scholar]
  111. 111. 
    Nie T, McDonough CB, Huang T, Nguyen PV, Abel T 2007. Genetic disruption of protein kinase A anchoring reveals a role for compartmentalized kinase signaling in theta-burst long-term potentiation and spatial memory. J. Neurosci. 27:10278–88
     [Google Scholar]
  112. 112. 
    Hoffman JR, Brandwein NJ, Nguyen PV 2019. Induction of β-adrenergic metaplasticity of LTP requires intact anchoring of PKA. Learn. Mem. 26:187–90
     [Google Scholar]
  113. 113. 
    Alto NM, Soderling SH, Hoshi N, Langeberg LK, Fayos R et al. 2003. Bioinformatic design of A-kinase anchoring protein-in silico: a potent and selective peptide antagonist of type II protein kinase A anchoring. PNAS 100:4445–50
     [Google Scholar]
  114. 114. 
    Gold MG, Lygren B, Dokurno P, Hoshi N, McConnachie G et al. 2006. Molecular basis of AKAP specificity for PKA regulatory subunits. Mol. Cell 24:383–95
     [Google Scholar]
  115. 115. 
    Faruque OM, Le-Nguyen D, Lajoix AD, Vives E, Petit P et al. 2009. Cell-permeable peptide-based disruption of endogenous PKA-AKAP complexes: a tool for studying the molecular roles of AKAP-mediated PKA subcellular anchoring. Am. J. Physiol. Cell Physiol. 296:C306–16
     [Google Scholar]
  116. 116. 
    Gold MG, Fowler DM, Means CK, Pawson CT, Stephany JJ et al. 2013. Engineering A-kinase anchoring protein (AKAP)-selective regulatory subunits of protein kinase A (PKA) through structure-based phage selection. J. Biol. Chem. 288:17111–21
     [Google Scholar]
  117. 117. 
    Singh M, Singh P, Vaira D, Torheim EA, Rahmouni S et al. 2014. The RIAD peptidomimetic inhibits HIV-1 replication in humanized NSG mice. Eur. J. Clin. Investig. 44:146–52
     [Google Scholar]
  118. 118. 
    Bendzunas NG, Dorfler S, Autenrieth K, Bertinetti D, Machal EMF et al. 2018. Investigating PKA-RII specificity using analogs of the PKA:AKAP peptide inhibitor STAD-2. Bioorg. Med. Chem. 26:1174–78
     [Google Scholar]
  119. 119. 
    Dostmann WR. 1995. (RP)-cAMPS inhibits the cAMP-dependent protein kinase by blocking the cAMP-induced conformational transition. FEBS Lett 375:231–34
     [Google Scholar]
  120. 120. 
    Rothermel JD, Perillo NL, Marks JS, Botelho LH 1984. Effects of the specific cAMP antagonist, (Rp)-adenosine cyclic 3′,5′-phosphorothioate, on the cAMP-dependent protein kinase-induced activity of hepatic glycogen phosphorylase and glycogen synthase. J. Biol. Chem. 259:15294–300
     [Google Scholar]
  121. 121. 
    Schachterle C, Christian F, Fernandes JM, Klussmann E 2015. Screening for small molecule disruptors of AKAP-PKA interactions. Methods Mol. Biol. 1294:151–66
     [Google Scholar]
  122. 122. 
    Christian F, Szaszak M, Friedl S, Drewianka S, Lorenz D et al. 2011. Small molecule AKAP-protein kinase A (PKA) interaction disruptors that activate PKA interfere with compartmentalized cAMP signaling in cardiac myocytes. J. Biol. Chem. 286:9079–96
     [Google Scholar]
  123. 123. 
    Carlson CR, Lygren B, Berge T, Hoshi N, Wong W et al. 2006. Delineation of type I protein kinase A-selective signaling events using an RI anchoring disruptor. J. Biol. Chem. 281:21535–45
     [Google Scholar]
  124. 124. 
    Burns-Hamuro LL, Ma Y, Kammerer S, Reineke U, Self C et al. 2003. Designing isoform-specific peptide disruptors of protein kinase A localization. PNAS 100:4072–77
     [Google Scholar]
  125. 125. 
    Nygren PJ, Scott JD. 2016. Regulation of the phosphatase PP2B by protein-protein interactions. Biochem. Soc. Trans. 44:1313–19
     [Google Scholar]
  126. 126. 
    Dell'Acqua ML, Dodge KL, Tavalin SJ, Scott JD 2002. Mapping the protein phosphatase-2B anchoring site on AKAP79. Binding and inhibition of phosphatase activity are mediated by residues 315–360. J. Biol. Chem. 277:48796–802
     [Google Scholar]
  127. 127. 
    Li J, Negro A, Lopez J, Bauman AL, Henson E et al. 2010. The mAKAPβ scaffold regulates cardiac myocyte hypertrophy via recruitment of activated calcineurin. J. Mol. Cell Cardiol. 48:387–94
     [Google Scholar]
  128. 128. 
    Nygren PJ, Mehta S, Schweppe DK, Langeberg LK, Whiting JL et al. 2017. Intrinsic disorder within AKAP79 fine-tunes anchored phosphatase activity toward substrates and drug sensitivity. eLife 6:e30872
     [Google Scholar]
  129. 129. 
    Clipstone NA, Crabtree GR. 1992. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature 357:695–97
     [Google Scholar]
  130. 130. 
    Liu J, Farmer JD Jr, Lane WL, Friedman J, Weissman I, Schreiber SL 1991. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66:807–15
     [Google Scholar]
  131. 131. 
    Aramburu J, Yaffe MB, Lopez-Rodriguez C, Cantley LC, Hogan PG, Rao A 1999. Affinity-driven peptide selection of an NFAT inhibitor more selective than cyclosporin A. Science 285:2129–33
     [Google Scholar]
  132. 132. 
    Matsoukas MT, Aranguren-Ibanez A, Lozano T, Nunes V, Lasarte JJ et al. 2015. Identification of small-molecule inhibitors of calcineurin-NFATc signaling that mimic the PxIxIT motif of calcineurin binding partners. Sci. Signal. 8:ra63
     [Google Scholar]
  133. 133. 
    Dotan N, Gayder V, Bloch I, Gal M 2018. An ELISA for the study of calcineurin-NFAT unstructured region interaction. Anal. Biochem. 549:66–71
     [Google Scholar]
  134. 134. 
    Westphal RS, Tavalin SJ, Lin JW, Alto NM, Fraser ID et al. 1999. Regulation of NMDA receptors by an associated phosphatase-kinase signaling complex. Science 285:93–96
     [Google Scholar]
  135. 135. 
    Bollen M, Peti W, Ragusa MJ, Beullens M 2010. The extended PP1 toolkit: designed to create specificity. Trends Biochem. Sci. 35:450–58
     [Google Scholar]
  136. 136. 
    Egloff MP, Johnson DF, Moorhead G, Cohen PTW, Cohen P, Barford D 1997. Structural basis for the recognition of regulatory subunits by the catalytic subunit of protein phosphatase 1. EMBO J 16:1876–87
     [Google Scholar]
  137. 137. 
    Ammosova T, Platonov M, Yedavalli VR, Obukhov Y, Gordeuk VR et al. 2012. Small molecules targeted to a non-catalytic “RVxF” binding site of protein phosphatase-1 inhibit HIV-1. PLOS ONE 7:e39481
     [Google Scholar]
  138. 138. 
    Ammosova T, Platonov M, Ivanov A, Kont YS, Kumari N et al. 2014. 1E7-03, a low MW compound targeting host protein phosphatase-1, inhibits HIV-1 transcription. Br. J. Pharmacol. 171:5059–75
     [Google Scholar]
  139. 139. 
    Lin X, Ammosova T, Choy MS, Pietzsch CA, Ivanov A et al. 2019. Targeting the non-catalytic RVxF site of protein phosphatase-1 with small molecules for Ebola virus inhibition. Front. Microbiol. 10:2145
     [Google Scholar]
  140. 140. 
    Mack K, Fischer MJM. 2017. Disrupting sensitization of TRPV4. Neuroscience 352:1–8
     [Google Scholar]
  141. 141. 
    Diviani D, Reggi E, Arambasic M, Caso S, Maric D 2016. Emerging roles of A-kinase anchoring proteins in cardiovascular pathophysiology. Biochim. Biophys. Acta Mol. Cell Res. 1863:1926–36
     [Google Scholar]
  142. 142. 
    Schrade K, Troger J, Eldahshan A, Zuhlke K, Abdul Azeez KR et al. 2018. An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells. PLOS ONE 13:e0191423
     [Google Scholar]
  143. 143. 
    Poelmans G, Franke B, Pauls DL, Glennon JC, Buitelaar JK 2013. AKAPs integrate genetic findings for autism spectrum disorders. Transl. Psychiatry 3:e270
     [Google Scholar]
  144. 144. 
    Reggi E, Diviani D. 2017. The role of A-kinase anchoring proteins in cancer development. Cell Signal 40:143–55
     [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-022420-112134
Loading
Drugs That Regulate Local Cell Signaling: AKAP Targeting as a Therapeutic Option
Annual Review of Pharmacology and Toxicology 61, 361 (2021); https://doi.org/10.1146/annurev-pharmtox-022420-112134
/content/journals/10.1146/annurev-pharmtox-022420-112134
/content/journals/10.1146/annurev-pharmtox-022420-112134
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error