Signalling scaffolds and local organization of cellular behaviour

Nature Reviews Molecular Cell Biology

Volumn 16, Issue 4, 2015, Pages 232-244

  Langeberg, Lorene K ^a   Scott, John D ^a  

^a UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLIC AMP DEPENDENT PROTEIN KINASE ANCHORING PROTEIN; HOLOENZYME; PSEUDOKINASE; PSEUDOPHOSPHATASE; SCAFFOLD PROTEIN; UNCLASSIFIED DRUG; NUCLEAR MATRIX PROTEIN;

ACETYLATION; CELL DIVISION; CELL FUNCTION; CELL MEMBRANE; CELL MOTION; CELL ORGANELLE; ENDOCRINE SYSTEM; ENZYME ACTIVATION; ENZYME ACTIVITY; HEART RATE; HORMONE ACTION; HUMAN; IN VITRO STUDY; IN VIVO STUDY; LONG TERM POTENTIATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN BINDING; PROTEIN CONFORMATION; PROTEIN DEPHOSPHORYLATION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; REVIEW; SIGNAL TRANSDUCTION; SYNAPTIC TRANSMISSION; UBIQUITINATION; ANIMAL; BIOLOGICAL MODEL; CELLS; ENZYMOLOGY; GENETICS; METABOLISM; REGULATOR GENE;

ANIMALS; CELL PHYSIOLOGICAL PHENOMENA; CELLS; GENES, SWITCH; HUMANS; MODELS, BIOLOGICAL; NUCLEAR MATRIX-ASSOCIATED PROTEINS; SIGNAL TRANSDUCTION;

EID: 84926207320     PISSN: 14710072     EISSN: 14710080     Source Type: Journal    
DOI: 10.1038/nrm3966     Document Type: Review

References (140)

1. Sadowski, I., Stone, J. C. & Pawson, T. A non-catalytic domain conserved among cytoplasmic protein-tyrosine kinases modifies the kinase function and transforming activity of Fujinami sarcoma virus P130gag-fps. Mol. Cell. Biol. 6, 4396-4408 (1986).
2. Pawson, T. Protein modules and signalling networks. Nature 373, 573-580 (1995).
3. Lemmon, M. A. & Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 141, 1117-1134 (2010).
4. Songyang, Z. & Cantley, L. C. Recognition and specificity in protein tyrosine kinase-mediated signalling. Trends Biochem. Sci. 20, 470-475 (1995).
5. Good, M. C., Zalatan, J. G. & Lim, W. A. Scaffold proteins: hubs for controlling the flow of cellular information. Science 332, 680-686 (2011).
6. Shaw, A. S., Kornev, A. P., Hu, J., Ahuja, L. G. & Taylor, S. S. Kinases and pseudokinases: lessons from RAF. Mol. Cell. Biol. 34, 1538-1546 (2014).
7. Fields, S. & Song, O. A novel genetic system to detect protein-protein interactions. Nature 340, 245-246 (1989).
8. Aebersold, R. & Mann, M. Mass spectrometry-based proteomics. Nature 422, 198-207 (2003).
9. Bowtell, D. D., Simon, M. A. & Rubin, G. M. Ommatidia in the developing Drosophila eye require and can respond to sevenless for only a restricted period. Cell 56, 931-936 (1989).
10. Simon, M. A., Bowtell, D. D., Dodson, G. S., Laverty, T. R. & Rubin, G. M. Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the sevenless protein tyrosine kinase. Cell 67, 701-716 (1991).
11. Friedman, A. & Perrimon, N. Genetic screening for signal transduction in the era of network biology. Cell 128, 225-231 (2007).
12. Pawson, T. & Scott, J. D. Signaling through scaffold, anchoring, and adaptor proteins. Science 278, 2075-2080 (1997).
13. Dodge-Kafka, K. L., Langeberg, L. & Scott, J. D. Compartmentation of cyclic nucleotide signaling in the heart: the role of A-kinase anchoring proteins. Circ. Res. 98, 993-1001 (2006).
14. Scott, J. D. & Pawson, T. Cell communication: the inside story. Sci. Am. 282, 72-79 (2000).
15. Lowenstein, E. J. et al. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell 70, 431-442 (1992).
16. Pelicci, G. et al. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell 70, 93-104 (1992).
17. Sun, X. J., Crimmins, D. L., Myers, M. G. J., Miralpeix, M. & White, M. F. Pleiotropic insulin signals are engaged by multisite phosphorylation of IRS-1. Mol. Cell. Biol. 13, 7418-7428 (1993).
18. Wolf, G. et al. PTB domains of IRS-1 and Shc have distinct but overlapping binding specificities. J. Biol. Chem. 270, 27407-27410 (1995).
19. Kouhara, H. et al. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/ MAPK signaling pathway. Cell 89, 693-702 (1997).
20. Bhattacharyya, R. P., Remenyi, A., Yeh, B. J. & Lim, W. A. Domains, motifs, and scaffolds: the role of modular interactions in the evolution and wiring of cell signaling circuits. Annu. Rev. Biochem. 75, 655-680 (2006).
21. Scott, J. D. & Pawson, T. Cell signaling in space and time: where proteins come together and when they're apart. Science 326, 1220-1224 (2009).
22. Boudeau, J., Miranda-Saavedra, D., Barton, G. J. & Alessi, D. R. Emerging roles of pseudokinases. Trends Cell Biol. 16, 443-452 (2006).
23. Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912-1934 (2002).
24. Manning, G., Plowman, G. D., Hunter, T. & Sudarsanam, S. Evolution of protein kinase signaling from yeast to man. Trends Biochem. Sci. 27, 514-520 (2002).
25. Egloff, M. P. et al. Structural basis for the recognition of regulatory subunits by the catalytic subunit of protein phosphatase 1. EMBO J. 16, 1876-1887 (1997).
26. Canagarajah, B. J., Khokhlatchev, A., Cobb, M. H. & Goldsmith, E. J. Activation mechanism of the MAP kinase ERK2 by dual phosphorylation. Cell 90, 859-869 (1997).
27. Schulze, W. X., Deng, L. & Mann, M. Phosphotyrosine interactome of the ErbB-receptor kinase family. Mol. Syst. Biol. 1, 2005.0008 (2005).
28. Zhang, X., Gureasko, J., Shen, K., Cole, P. A. & Kuriyan, J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 125, 1137-1149 (2006).
29. Hemminki, A. et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391, 184-187 (1998).
30. Shaw, R. J. LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol. 196, 65-80 (2009).
31. Zheng, B. & Cantley, L. C. Regulation of epithelial tight junction assembly and disassembly by AMP-activated protein kinase. Proc. Natl Acad. Sci. USA 104, 819-822 (2007).
32. Boudeau, J. et al. MO25α/β interact with STRADα/β enhancing their ability to bind, activate and localize LKB1 in the cytoplasm. EMBO J. 22, 5102-5114 (2003).
33. Zeqiraj, E., Filippi, B. M., Deak, M., Alessi, D. R. & van Aalten, D. M. Structure of the LKB1-STRAD- MO25 complex reveals an allosteric mechanism of kinase activation. Science 326, 1707-1711 (2009).
34. Rajakulendran, T. & Sicheri, F. Allosteric protein kinase regulation by pseudokinases: insights from STRAD. Sci. Signal. 3, pe8 (2010).
35. Zeqiraj, E. et al. ATP and MO25α regulate the conformational state of the STRADα pseudokinase and activation of the LKB1 tumour suppressor. PLoS Biol. 7, e1000126 (2009).
36. Morrison, D. K. KSR: a MAPK scaffold of the Ras pathway? J. Cell Sci. 114, 1609-1612 (2001).
37. McKay, M. M., Ritt, D. A. & Morrison, D. K. RAF inhibitor-induced KSR1/B-RAF binding and its effects on ERK cascade signaling. Curr. Biol. 21, 563-568 (2011).
38. Brennan, D. F. et al. A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK. Nature 472, 366-369 (2011).
39. Smith, F. D. et al. AKAP-Lbc enhances cyclic AMP control of the ERK1/2 cascade. Nature Cell Biol. 12, 1242-1249 (2010).
40. Hu, J. et al. Mutation that blocks ATP binding creates a pseudokinase stabilizing the scaffolding function of kinase suppressor of Ras, CRAF and BRAF. Proc. Natl Acad. Sci. USA 108, 6067-6072 (2011).
41. Poulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M. & Rosen, N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464, 427-430 (2010).
42. Hu, J. et al. Allosteric activation of functionally asymmetric RAF kinase dimers. Cell 154, 1036-1046 (2013).
43. Wishart, M. J., Denu, J. M., Williams, J. A. & Dixon, J. E. A single mutation converts a novel phosphotyrosine binding domain into a dual-specificity phosphatase. J. Biol. Chem. 270, 26782-26785 (1995).
44. Tonks, N. K. Pseudophosphatases: grab and hold on. Cell 139, 464-465 (2009).
45. Cheng, K. C., Klancer, R., Singson, A. & Seydoux, G. Regulation of MBK-2/DYRK by CDK-1 and the pseudophosphatases EGG-4 and EGG-5 during the oocyte-to-embryo transition. Cell 139, 560-572 (2009).
46. Parry, J. M. et al. EGG-4 and EGG-5 link events of the oocyte-to-embryo transition with meiotic progression in C. elegans. Curr. Biol. 19, 1752-1757 (2009).
47. Reiterer, V., Fey, D., Kolch, W., Kholodenko, B. N. & Farhan, H. Pseudophosphatase STYX modulates cell-fate decisions and cell migration by spatiotemporal regulation of ERK1/2. Proc. Natl Acad. Sci. USA 110, E2934-E2943 (2013).
48. Scott, J. D. et al. Type II regulatory subunit dimerization determines the subcellular localization of the cAMP-dependent protein kinase. J. Biol. Chem. 265, 21561-21566 (1990).
49. Luo, Z., Shafit-Zagardo, B. & Erlichman, J. Identification of the MAP2- and P75- binding domain in the regulatory subunit (RIIβ) of type II cAMP-dependent protein kinase. J. Biol. Chem. 265, 21804-21810 (1990).
50. Carr, D. W. et al. Interaction of the regulatory subunit (RII) of cAMP-dependent protein kinase with RII-anchoring proteins occurs through an amphipathic helix binding motif. J. Biol. Chem. 266, 14188-14192 (1991).
51. Rubin, C. S. A kinase anchor proteins and the intracellular targeting of signals carried by cAMP. Biochim. Biophys. Acta 1224, 467-479 (1994).
52. Tasken, K. & Aandahl, E. M. Localized effects of cAMP mediated by distinct routes of protein kinase A. Physiol. Rev. 84, 137-167 (2004).
53. Welch, E. J., Jones, B. W. & Scott, J. D. Networking with AKAPs: context-dependent regulation of anchored enzymes. Mol. Interv. 10, 86-97 (2010).
54. Wong, W. & Scott, J. D. AKAP signalling complexes: focal points in space and time. Nature Rev. Mol. Cell Biol. 5, 959-971 (2004).
55. Smith, F. D. et al. Intrinsic disorder within an AKAP-protein kinase A complex guides local substrate phosphorylation. eLife 2, e01319 (2013).
56. Newlon, M. G. et al. The molecular basis for protein kinase A anchoring revealed by solution NMR. Nature Struct. Biol. 6, 222-227 (1999).
57. Gold, M. G. et al. Molecular basis of AKAP specificity for PKA regulatory subunits. Mol. Cell 24, 383-395 (2006).
58. Kinderman, F. S. et al. A dynamic mechanism for AKAP binding to RII isoforms of cAMP-dependent protein kinase. Mol. Cell 24, 397-408 (2006).
59. Sarma, G. N. et al. Structure of D-AKAP2:PKA RI complex: insights into AKAP specificity and selectivity. Structure 18, 155-166 (2010).
60. Carr, D. W., Hausken, Z. E., Fraser, I. D., Stofko-Hahn, R. E. & Scott, J. D. 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, 13376-13382 (1992).
61. Lester, L. B., Coghlan, V. M., Nauert, B. & Scott, J. D. Cloning and characterization of a novel A-kinase anchoring protein: AKAP220, association with testicular peroxisomes. J. Biol. Chem. 272, 9460-9465 (1996).
62. Gao, S., Wang, H. Y. & Malbon, C. C. AKAP12 and AKAP5 form higher-order hetero-oligomers. J. Mol. Signal. 6, 8 (2011).
63. Gold, M. G. et al. Engineering A-kinase anchoring protein (AKAP)-selective regulatory subunits of protein kinase A (PKA) through structure-based phage selection. J. Biol. Chem. 288, 17111-17121 (2013).
64. Carr, D. W., Stofko-Hahn, R. E., Fraser, I. D. C., Cone, R. D. & Scott, J. D. Localization of the cAMP-dependent protein kinase to the postsynaptic densities by A-kinase anchoring proteins: characterization of AKAP79. J. Biol. Chem. 24, 16816-16823 (1992).
65. Coghlan, V. M. et al. Association of protein kinase A and protein phosphatase 2B with a common anchoring protein. Science 267, 108-112 (1995).
66. Klauck, T. M. et al. Coordination of three signaling enzymes by AKAP79, a mammalian scaffold protein. Science 271, 1589-1592 (1996).
67. Hoshi, N., Langeberg, L. K. & Scott, J. D. Distinct enzyme combinations in AKAP signalling complexes permit functional diversity. Nature Cell Biol. 7, 1066-1073 (2005).
68. Huganir, R. L. & Nicoll, R. A. AMPARs and synaptic plasticity: the last 25 years. Neuron 80, 704-717 (2013).
69. Tavalin, S. J. et al. Regulation of GluR1 by the A-kinase anchoring protein 79 (AKAP79) signaling complex shares properties with long-term depression. J. Neurosci. 22, 3044-3051 (2002).
70. Sanderson, J. L. et al. AKAP150-anchored calcineurin regulates synaptic plasticity by limiting synaptic incorporation of Ca2+-permeable AMPA receptors. J. Neurosci. 32, 15036-15052 (2012).
71. Suh, B. C., Inoue, T., Meyer, T. & Hille, B. Rapid chemically induced changes of PtdIns(4, 5)P2 gate KCNQ ion channels. Science 314, 1454-1457 (2006).
72. Hoshi, N. et al. AKAP150 signaling complex promotes suppression of the M-current by muscarinic agonists. Nature Neurosci. 6, 564-571 (2003).
73. Tunquist, B. J. et al. Loss of AKAP150 perturbs distinct neuronal processes in mice. Proc. Natl Acad. Sci. USA 105, 12557-12562 (2008).
74. Hoshi, N., Langeberg, L. K., Gould, C. M., Newton, A. C. & Scott, J. D. Interaction with AKAP79 modifies the cellular pharmacology of PKC. Mol. Cell 37, 541-550 (2010).
75. Dyachok, O., Isakov, Y., Sagetorp, J. & Tengholm, A. Oscillations of cyclic AMP in hormone-stimulated insulin-secreting β-cells. Nature 439, 349-352 (2006).
76. Lester, L. B., Faux, M. C., Nauert, J. B. & Scott, J. D. Targeted protein kinase A and PP-2B regulate insulin secretion through reversible phosphorylation. Endocrinology 142, 1218-1227 (2001).
77. Bauman, A. L. et al. Dynamic regulation of cAMP synthesis through anchored PKA-adenylyl cyclase V/VI complexes. Mol. Cell 23, 925-931 (2006).
78. Dessauer, C. W. Adenylyl cyclase - A-kinase anchoring protein complexes: the next dimension in cAMP signaling. Mol. Pharmacol. 76, 935-941 (2009).
79. Hinke, S. A. et al. Anchored phosphatases modulate glucose homeostasis. EMBO J. 31, 3991-4004 (2012).
80. Cohen, P. The origins of protein phosphorylation. Nature Cell Biol. 4, E127-E130 (2002).
81. Cohen, P. T. Protein phosphatase 1 - targeted in many directions. J. Cell Sci. 115, 241-256 (2002).
82. Vazquez-Martin, C., Rouse, J. & Cohen, P. T. Characterization of the role of a trimeric protein phosphatase complex in recovery from cisplatin-induced versus noncrosslinking DNA damage. FEBS J. 275, 4211-4221 (2008).
83. Bollen, M. Combinatorial control of protein phosphatase-1. Trends Biochem. Sci. 26, 426-431 (2001).
84. Hendrickx, A. et al. Docking motif-guided mapping of the interactome of protein phosphatase-1. Chem. Biol. 16, 365-371 (2009).
85. De Munter, S., Kohn, M. & Bollen, M. Challenges and opportunities in the development of protein phosphatase-directed therapeutics. ACS Chem. Biol. 8, 36-45 (2013).
86. Hartshorne, D. J. & Hirano, K. Interactions of protein phosphatase type 1, with a focus on myosin phosphatase. Mol. Cell. Biochem. 190, 79-84 (1999).
87. Surks, H. K. et al. Regulation of myosin phosphatase by a specific interaction with cGMP-dependent protein kinase Iα. Science 286, 1583-1587 (1999).
88. Lincoln, T. M. Myosin phosphatase regulatory pathways: different functions or redundant functions? Circ. Res. 100, 10-12 (2007).
89. Matsumura, F. & Hartshorne, D. J. Myosin phosphatase target subunit: many roles in cell function. Biochem. Biophys. Res. Commun. 369, 149-156 (2008).
90. Lee, M. R., Li, L. & Kitazawa, T. Cyclic GMP causes Ca2+ desensitization in vascular smooth muscle by activating the myosin light chain phosphatase. J. Biol. Chem. 272, 5063-5068 (1997).
91. Kaneko-Kawano, T. et al. Dynamic regulation of myosin light chain phosphorylation by Rho-kinase. PLoS ONE 7, e39269 (2012).
92. McKay, M. M. & Morrison, D. K. Integrating signals from RTKs to ERK/MAPK. Oncogene 26, 3113-3121 (2007).
93. Malumbres, M. & Barbacid, M. RAS oncogenes: the first 30 years. Nature Rev. Cancer 3, 459-465 (2003).
94. Cordeddu, V. et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nature Genet. 41, 1022-1026 (2009).
95. Young, L. C. et al. An MRAS, SHOC2, and SCRIB complex coordinates ERK pathway activation with polarity and tumorigenic growth. Mol. Cell 52, 679-692 (2013).
96. Rodriguez-Viciana, P., Oses-Prieto, J., Burlingame, A., Fried, M. & McCormick, F. A phosphatase holoenzyme comprised of Shoc2/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity. Mol. Cell 22, 217-230 (2006).
97. Wolff, S., Weissman, J. S. & Dillin, A. Differential scales of protein quality control. Cell 157, 52-64 (2014).
98. Grabbe, C. & Dikic, I. Cell biology. Going global on ubiquitin. Science 322, 872-873 (2008).
99. Shaid, S., Brandts, C. H., Serve, H. & Dikic, I. Ubiquitination and selective autophagy. Cell. Death Differ. 20, 21-30 (2013).
100. Gardner, R. G., Nelson, Z. W. & Gottschling, D. E. Degradation-mediated protein quality control in the nucleus. Cell 120, 803-815 (2005).
101. Rosenbaum, J. C. et al. Disorder targets misorder in nuclear quality control degradation: a disordered ubiquitin ligase directly recognizes its misfolded substrates. Mol. Cell 41, 93-106 (2011).
102. Frescas, D. & Pagano, M. Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancer. Nature Rev. Cancer 8, 438-449 (2008).
103. Singh, B. N. et al. Nonhistone protein acetylation as cancer therapy targets. Expert Rev. Anticancer Ther. 10, 935-954 (2010).
104. Suganuma, T. et al. ATAC is a double histone acetyltransferase complex that stimulates nucleosome sliding. Nature Struct. Mol. Biol. 15, 364-372 (2008).
105. Suganuma, T. et al. The ATAC acetyltransferase complex coordinates MAP kinases to regulate JNK target genes. Cell 142, 726-736 (2010).
106. Jiang, W. et al. Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. Mol. Cell 43, 33-44 (2011).
107. Choudhary, C. et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325, 834-840 (2009).
108. Wang, Q. et al. Acetylation of metabolic enzymes coordinates carbon source utilization and metabolic flux. Science 327, 1004-1007 (2010).
109. Zhao, S. et al. Regulation of cellular metabolism by protein lysine acetylation. Science 327, 1000-1004 (2010).
110. Kranz, J. E., Satterberg, B. & Elion, E. A. The MAP kinase Fus3 associates with and phosphorylates the upstream signaling component Ste5. Genes Dev. 8, 313-327 (1994).
111. Sette, C., Inouye, C. J., Stroschein, S. L., Iaquinta, P. J. & Thorner, J. Mutational analysis suggests that activation of the yeast pheromone response mitogen-activated protein kinase pathway involves conformational changes in the Ste5 scaffold protein. Mol. Biol. Cell 11, 4033-4049 (2000).
112. Elion, E. A. The Ste5p scaffold. J. Cell Sci. 114, 3967-3978 (2001).
113. Strickfaden, S. C. et al. A mechanism for cell-cycle regulation of MAP kinase signaling in a yeast differentiation pathway. Cell 128, 519-531 (2007).
114. Malleshaiah, M. K., Shahrezaei, V., Swain, P. S. & Michnick, S. W. The scaffold protein Ste5 directly controls a switch-like mating decision in yeast. Nature 465, 101-105 (2010).
115. Zalatan, J. G., Coyle, S. M., Rajan, S., Sidhu, S. S. & Lim, W. A. Conformational control of the Ste5 scaffold protein insulates against MAP kinase misactivation. Science 337, 1218-1222 (2012).
116. Whitmarsh, A. J., Cavanagh, J., Tournier, C., Yasuda, J. & Davis, R. J. A mammalian scaffold complex that selectively mediates MAP kinase activation. Science 281, 1671-1674 (1998).
117. Bonny, C., Nicod, P. & Waeber, G. IB1, a JIP-1-related nuclear protein present in insulin-secreting cells. J. Biol. Chem. 273, 1843-1846 (1998).
118. Fu, M. M. & Holzbaur, E. L. JIP1 regulates the directionality of APP axonal transport by coordinating kinesin and dynein motors. J. Cell Biol. 202, 495-508 (2013).
119. Willoughby, E. A., Perkins, G. R., Collins, M. K. & Whitmarsh, A. J. The JNK-interacting protein-1 scaffold protein targets MAPK phosphatase-7 to dephosphorylate JNK. J. Biol. Chem. 278, 10731-10736 (2003).
120. Fu, M. M., Nirschl, J. J. & Holzbaur, E. L. LC3 binding to the scaffolding protein JIP1 regulates processive dynein-driven transport of autophagosomes. Dev. Cell 29, 577-590 (2014).
121. Robinson, C. V., Sali, A. & Baumeister, W. The molecular sociology of the cell. Nature 450, 973-982 (2007).
122. Heck, A. J. Native mass spectrometry: a bridge between interactomics and structural biology. Nature Methods 5, 927-933 (2008).
123. Gold, M. G. et al. Architecture and dynamics of an A-kinase anchoring protein 79 (AKAP79) signaling complex. Proc. Natl Acad. Sci. USA 108, 6426-6431 (2011).
124. Jain, A. et al. Probing cellular protein complexes using single-molecule pull-down. Nature 473, 484-488 (2011).
125. Means, C. K. et al. An entirely specific type I A-kinase anchoring protein that can sequester two molecules of protein kinase A at mitochondria. Proc. Natl Acad. Sci. USA 108, E1227-E1235 (2011).
126. Cao, E., Liao, M., Cheng, Y. & Julius, D. TRPV1 structures in distinct conformations reveal activation mechanisms. Nature 504, 113-118 (2013).
127. Li, X. et al. Electron counting and beam-induced motion correction enable near-atomic-resolution single-particle cryo-EM. Nature Methods 10, 584-590 (2013).
128. Bai, X. C., Fernandez, I. S., McMullan, G. & Scheres, S. H. Ribosome structures to near-atomic resolution from thirty thousand cryo-EM particles. eLife 2, e00461 (2013).
129. Lu, P. et al. Three-dimensional structure of human ?-secretase. Nature 512, 166-170 (2014).
130. Scheres, S. H. Beam-induced motion correction for sub-megadalton cryo-EM particles. eLife 3, e03665 (2014).
131. Fernandez-Medarde, A. & Santos, E. Ras in cancer and developmental diseases. Genes Cancer 2, 344-358 (2011).
132. Hatzivassiliou, G. et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464, 431-435 (2010).
133. Halaban, R. et al. PLX4032, a selective BRAFV600E kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAFWT melanoma cells. Pigment Cell Melanoma Res. 23, 190-200 (2010).
134. Rubinstein, J. C. et al. Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J. Transl. Med. 8, 67 (2010).
135. Reiterer, V., Eyers, P. A. & Farhan, H. Day of the dead: pseudokinases and pseudophosphatases in physiology and disease. Trends Cell Biol. 24, 489-505 (2014).
136. Shi, F. & Lemmon, M. A. KSR plays CRAF-ty. Science 332, 1043-1044 (2011).
137. Carnegie, G. K., Means, C. K. & Scott, J. D. A-kinase anchoring proteins: from protein complexes to physiology and disease. IUBMB Life 61, 394-406 (2009).
138. Li, H. et al. Balanced interactions of calcineurin with AKAP79 regulate Ca2+-calcineurin-NFAT signaling. Nature Struct. Mol. Biol. 19, 337-345 (2012).
139. Morrison, D. K. & Davis, R. J. Regulation of MAP kinase signaling modules by scaffold proteins in mammals. Annu. Rev. Cell Dev. Biol. 19, 91-118 (2003).
140. Scholten, A. et al. Analysis of the cGMP/cAMP interactome using a chemical proteomics approach in mammalian heart tissue validates sphingosine kinase type 1-interacting protein as a genuine and highly abundant AKAP. J. Proteome Res. 5, 1435-1447 (2006).