Regulatory crosstalk by protein kinases on CFTR trafficking and activity

Frontiers in Chemistry

Volumn 4, Issue JAN, 2016, Pages

  Farinha, Carlos M ^a   Swiatecka Urban, Agnieszka ^b,c   Brautigan, David L ^d   Jordan, Peter ^a,e  

^a UNIVERSITY OF LISBON   (Portugal)

^b UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^c CHILDREN S HOSPITAL OF PITTSBURGH   (United States)

^d UNIVERSITY OF VIRGINIA   (United States)

^e NATIONAL INSTITUTE OF HEALTH DR RICARDO JORGE   (Portugal)

Author keywords

CFTR; Cystic fibrosis; Kinase; Phosphorylation; Protein trafficking

Indexed keywords

EID: 84969528840     PISSN: None     EISSN: 22962646     Source Type: Journal    
DOI: 10.3389/fchem.2016.00001     Document Type: Review

References (107)

1. Alzamora, R., King, J. D. Jr., and Hallows, K. R. (2011). CFTR regulation by phosphorylation. Methods Mol. Biol. 741, 471-488. doi: 10.1007/978-1-61779-117-8_29
2. Amaral, M. D. (2005). Processing of CFTR: traversing the cellular maze-how much CFTR needs to go through to avoid cystic fibrosis? Pediatr. Pulmonol. 39, 479-491. doi: 10.1002/ppul.20168
3. Amaral, M. D., and Farinha, C. M. (2013). Rescuing mutant CFTR: a multi-task approach to a better outcome in treating cystic fibrosis. Curr. Pharm. Des. 19, 3497-3508. doi: 10.2174/13816128113199990318
4. Ameen, N., Silvis, M., and Bradbury, N. A. (2007). Endocytic trafficking of CFTR in health and disease. J. Cyst. Fibr. 6, 1-14. doi: 10.1016/j.jcf.2006.09.002
5. Anderson, M. P., Berger, H. A., Rich, D. P., Gregory, R. J., Smith, A. E., and Welsh, M. J. (1991). Nucleoside triphosphates are required to open the CFTR chloride channel. Cell 67, 775-784. doi: 10.1016/0092-8674(91)90072-7
6. Berger, H. A., Travis, S. M., and Welsh, M. J. (1993). Regulation of the cystic fibrosis transmembrane conductance regulator Cl- channel by specific protein kinases and protein phosphatases. J. Biol. Chem. 268, 2037-2047.
7. Billet, A., Jia, Y., Jensen, T., Riordan, J. R., and Hanrahan, J. W. (2015a). Regulation of the cystic fibrosis transmembrane conductance regulator anion channel by tyrosine phosphorylation. FASEB J. 29, 3945-3953. doi: 10.1096/fj.15-273151
8. Billet, A., Jia, Y., Jensen, T. J., Hou, Y. X., Chang, X. B., Riordan, J. R., et al. (2015b). Potential sites of CFTR activation by tyrosine kinases. Channels (Austin). doi: 10.1080/19336950.2015.1126010
9. Cai, H., Cebotaru, V., Wang, Y. H., Zhang, X. M., Cebotaru, L., Guggino, S. E., et al. (2006). WNK4 kinase regulates surface expression of the human sodium chloride cotransporter in mammalian cells. Kidney Int. 69, 2162-2170. doi: 10.1038/sj.ki.5000333
10. Cesaro, L., Marin, O., Venerando, A., Donella-Deana, A., and Pinna, L. A. (2013). Phosphorylation of cystic fibrosis transmembrane conductance regulator (CFTR) serine-511 by the combined action of tyrosine kinases and CK2: the implication of tyrosine-512 and phenylalanine-508. Amino Acids 45, 1423-1429. doi: 10.1007/s00726-013-1613-y
11. Cha, S. K., and Huang, C. L. (2010). WNK4 kinase stimulates caveola-mediated endocytosis of TRPV5 amplifying the dynamic range of regulation of the channel by protein kinase C. J. Biol. Chem. 285, 6604-6611. doi: 10.1074/jbc.M109.056044
12. Chappe, V., Hinkson, D. A., Howell, L. D., Evagelidis, A., Liao, J., Chang, X. B., et al. (2004). Stimulatory and inhibitory protein kinase C consensus sequences regulate the cystic fibrosis transmembrane conductance regulator. Proc. Natl. Acad. Sci. U.S.A. 101, 390-395. doi: 10.1073/pnas.0303411101
13. Cheng, S. H., Gregory, R. J., Marshall, J., Paul, S., Souza, D. W., White, G. A., et al. (1990). Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell 63, 827-834. doi: 10.1016/0092-8674(90)90148-8
14. Cheng, S. H., Rich, D. P., Marshall, J., Gregory, R. J., Welsh, M. J., and Smith, A. E. (1991). Phosphorylation of the R domain by cAMP-dependent protein kinase regulates the CFTR chloride channel. Cell 66, 1027-1036. doi: 10.1016/0092-8674(91)90446-6
15. Chibalina, M. V., Seaman, M. N., Miller, C. C., Kendrick-Jones, J., and Buss, F. (2007). Myosin VI and its interacting protein LMTK2 regulate tubule formation and transport to the endocytic recycling compartment. J. Cell Sci. 120, 4278-4288. doi: 10.1242/jcs.014217
16. Choate, K. A., Kahle, K. T., Wilson, F. H., Nelson-Williams, C., and Lifton, R. P. (2003). WNK1, a kinase mutated in inherited hypertension with hyperkalemia, localizes to diverse Cl- -transporting epithelia. Proc. Natl. Acad. Sci. U.S.A. 100, 663-668. doi: 10.1073/pnas.242728499
17. Chung, W. Y., Park, H. W., Han, J. W., Lee, M. G., and Kim, J. Y. (2013). WNK4 inhibits plasma membrane targeting of NCC through regulation of syntaxin13 SNARE formation. Cell. Signal. 25, 2469-2477. doi: 10.1016/j.cellsig.2013.08.006
18. Cihil, K. M., Zimnik, A., and Swiatecka-Urban, A. (2013). c-Cbl reduces stability of rescued F508-CFTR in human airway epithelial cells: implications for cystic fibrosis treatment. Commun. Integr. Biol. 6, e23094. doi: 10.4161/cib.23094
19. Clancy, J. P., Rowe, S. M., Accurso, F. J., Aitken, M. L., Amin, R. S., Ashlock, M. A., et al. (2012). Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax 67, 12-18. doi: 10.1136/thoraxjnl-2011-200393
20. Cope, G., Murthy, M., Golbang, A. P., Hamad, A., Liu, C. H., Cuthbert, A. W., et al. (2006). WNK1 affects surface expression of the ROMK potassium channel independent of WNK4. J. Am. Soc. Nephrol. 17, 1867-1874. doi: 10.1681/ASN.2005111224
21. De Stefano, D., Villella, V. R., Esposito, S., Tosco, A., Sepe, A., De Gregorio, F., et al. (2014). Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation. Autophagy 10, 2053-2074. doi: 10.4161/15548627.2014.973737
22. Dirac-Svejstrup, A. B., Shorter, J., Waters, M. G., and Warren, G. (2000). Phosphorylation of the vesicle-tethering protein p115 by a casein kinase II-like enzyme is required for Golgi reassembly from isolated mitotic fragments. J. Cell Biol. 150, 475-488. doi: 10.1083/jcb.150.3.475
23. Farfel, Z., Mayan, H., Yaacov, Y., Mouallem, M., Shaharabany, M., Pauzner, R., et al. (2005). WNK4 regulates airway Na+ transport: study of familial hyperkalaemia and hypertension. Eur. J. Clin. Invest. 35, 410-415. doi: 10.1111/j.1365-2362.2005.01504.x
24. Farinha, C. M., and Amaral, M. D. (2005). Most F508del-CFTR is targeted to degradation at an early folding checkpoint and independently of calnexin. Mol. Cell. Biol. 25, 5242-5252. doi: 10.1128/MCB.25.12.5242-5252.2005
25. Farinha, C. M., Nogueira, P., Mendes, F., Penque, D., and Amaral, M. D. (2002). The human DnaJ homologue (Hdj)-1/heat-shock protein (Hsp) 40 co-chaperone is required for the in vivo stabilization of the cystic fibrosis transmembrane conductance regulator by Hsp70. Biochem. J. 366, 797-806. doi: 10.1042/bj20011717
26. Fu, A. K., Fu, W. Y., Cheung, J., Tsim, K. W., Ip, F. C., Wang, J. H., et al. (2001). Cdk5 is involved in neuregulin-induced AChR expression at the neuromuscular junction. Nat. Neurosci. 4, 374-381. doi: 10.1038/86019
27. Gamba, G. (2005). Role of WNK kinases in regulating tubular salt and potassium transport and in the development of hypertension. Am. J. Physiol. Renal Physiol. 288, F245-F252. doi: 10.1152/ajprenal.00311.2004
28. Gasparrini, F., Molfetta, R., Quatrini, L., Frati, L., Santoni, A., and Paolini, R. (2012). Syk-dependent regulation of Hrs phosphorylation and ubiquitination upon FcepsilonRI engagement: impact on Hrs membrane/cytosol localization. Eur. J. Immunol. 42, 2744-2753. doi: 10.1002/eji.201142278
29. Glozman, R., Okiyoneda, T., Mulvihill, C. M., Rini, J. M., Barriere, H., and Lukacs, G. L. (2009). N-glycans are direct determinants of CFTR folding and stability in secretory and endocytic membrane traffic. J. Cell Biol. 184, 847-862. doi: 10.1083/jcb.200808124
30. Greenberg, S. (1999). Modular components of phagocytosis. J. Leukoc. Biol. 66, 712-717.
31. Hallows, K. R., Raghuram, V., Kemp, B. E., Witters, L. A., and Foskett, J. K. (2000). Inhibition of cystic fibrosis transmembrane conductance regulator by novel interaction with the metabolic sensor AMP-activated protein kinase. J. Clin. Invest. 105, 1711-1721. doi: 10.1172/JCI9622
32. Hanks, S. K. (2003). Genomic analysis of the eukaryotic protein kinase superfamily: a perspective. Genome Biol. 4:111. doi: 10.1186/gb-2003-4-5-111
33. Hanyaloglu, A. C., Vrecl, M., Kroeger, K. M., Miles, L. E., Qian, H., Thomas, W. G., et al. (2001). Casein kinase II sites in the intracellular C-terminal domain of the thyrotropin-releasing hormone receptor and chimeric gonadotropin-releasing hormone receptors contribute to beta-arrestin-dependent internalization. J. Biol. Chem. 276, 18066-18074. doi: 10.1074/jbc.M009275200
34. Harries, L. W., Perry, J. R., McCullagh, P., and Crundwell, M. (2010). Alterations in LMTK2, MSMB and HNF1B gene expression are associated with the development of prostate cancer. BMC Cancer 10:315. doi: 10.1186/1471-2407-10-315
35. He, G., Wang, H. R., Huang, S. K., and Huang, C. L. (2007). Intersectin links WNK kinases to endocytosis of ROMK1. J. Clin. Invest. 117, 1078-1087. doi: 10.1172/JCI30087
36. Heda, G. D., Tanwani, M., and Marino, C. R. (2001). The Delta F508 mutation shortens the biochemical half-life of plasma membrane CFTR in polarized epithelial cells. Am. J. Physiol. Cell Physiol. 280, C166-C174. Available online at: http://ajpcell.physiology.org/content/280/1/C166.long
37. Heda, G. D., Tanwani, M., and Marino, C. R. (2001). The Delta F508 mutation shortens the biochemical half-life of plasma membrane CFTR in polarized epithelial cells. Am. J. Physiol. Cell Physiol. 280, C166-C174. Available online at: http://ajpcell.physiology.org/content/280/1/C166.long
38. Higgins, C. F. (1992a). ABC transporters: from microorganisms to man. Annu. Rev. Cell Biol. 8, 67-113. doi: 10.1146/annurev.cb.08.110192.000435
39. Higgins, C. F. (1992b). Cystic fibrosis transmembrane conductance regulator (CFTR). Br. Med. Bull. 48, 754-765.
40. Holleran, J. P., Zeng, J., Frizzell, R. A., and Watkins, S. C. (2013). Regulated recycling of mutant CFTR is partially restored by pharmacological treatment. J. Cell Sci. 126, 2692-2703. doi: 10.1242/jcs.120196
41. Inoue, T., Kon, T., Ohkura, R., Yamakawa, H., Ohara, O., Yokota, J., et al. (2008). BREK/LMTK2 is a myosin VI-binding protein involved in endosomal membrane trafficking. Genes Cells 13, 483-495. doi: 10.1111/j.1365-2443.2008.01184.x
42. Jia, Y., Mathews, C. J., and Hanrahan, J. W. (1997). Phosphorylation by protein kinase C is required for acute activation of cystic fibrosis transmembrane conductance regulator by protein kinase A. J. Biol. Chem. 272, 4978-4984. doi: 10.1074/jbc.272.8.4978
43. Kahle, K. T., Rinehart, J., Ring, A., Gimenez, I., Gamba, G., Hebert, S. C., et al. (2006). WNK protein kinases modulate cellular Cl- flux by altering the phosphorylation state of the Na-K-Cl and K-Cl cotransporters. Physiology (Bethesda) 21, 326-335. doi: 10.1152/physiol.00015.2006
44. Kahle, K. T., Ring, A. M., and Lifton, R. P. (2008). Molecular physiology of the WNK kinases. Annu. Rev. Physiol. 70, 329-355. doi: 10.1146/annurev.physiol.70.113006.100651
45. Kahle, K. T., Wilson, F. H., Lalioti, M., Toka, H., Qin, H., and Lifton, R. P. (2004). WNK kinases: molecular regulators of integrated epithelial ion transport. Curr. Opin. Nephrol. Hypertens. 13, 557-562. doi: 10.1097/00041552-200409000-00012
46. Kahle, K. T., Wilson, F. H., Leng, Q., Lalioti, M. D., O'Connell, A. D., Dong, K., et al. (2003). WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion. Nat. Genet. 35, 372-376. doi: 10.1038/ng1271
47. Kawa, S., Fujimoto, J., Tezuka, T., Nakazawa, T., and Yamamoto, T. (2004). Involvement of BREK, a serine/threonine kinase enriched in brain, in NGF signalling. Genes Cells 9, 219-232. doi: 10.1111/j.1356-9597.2004.00714.x
48. Ko, B., Mistry, A., Hanson, L., Mallick, R., and Hoover, R. S. (2015). Mechanisms of angiotensin II stimulation of NCC are time-dependent in mDCT15 cells. Am. J. Physiol. Renal Physiol. 308, F720-F727. doi: 10.1152/ajprenal.00465.2014
49. Kongsuphol, P., Cassidy, D., Hieke, B., Treharne, K. J., Schreiber, R., Mehta, A., et al. (2009). Mechanistic insight into control of CFTR by AMPK. J. Biol. Chem. 284, 5645-5653. doi: 10.1074/jbc.M806780200
50. Koreishi, M., Yu, S., Oda, M., Honjo, Y., and Satoh, A. (2013). CK2 phosphorylates Sec31 and regulates ER-To-Golgi trafficking. PLoS ONE 8:e54382. doi: 10.1371/journal.pone.0054382
51. Lazrak, A., Liu, Z., and Huang, C. L. (2006). Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms. Proc. Natl. Acad. Sci. U.S.A. 103, 1615-1620. doi: 10.1073/pnas.0510609103
52. Lew, J., Huang, Q. Q., Qi, Z., Winkfein, R. J., Aebersold, R., Hunt, T., et al. (1994). A brain-specific activator of cyclin-dependent kinase 5. Nature 371, 423-426. doi: 10.1038/371423a0
53. Lukashova, V., Szabó, E. Z., Jinadasa, T., Mokhov, A., Litchfield, D. W., and Orlowski, J. (2011). CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis. J. Biol. Chem. 286, 11456-11468. doi: 10.1074/jbc.M110.182881
54. Luz, S., Cihil, K. M., Brautigan, D. L., Amaral, M. D., Farinha, C. M., and Swiatecka-Urban, A. (2014). LMTK2 Mediated Phosphorylation Regulates CFTR Endocytosis in Human Airway Epithelial Cells. J. Biol. Chem. 280, 15080-15093. doi: 10.1074/jbc.M114.563742
55. Luz, S., Kongsuphol, P., Mendes, A. I., Romeiras, F., Sousa, M., Schreiber, R., et al. (2011). Contribution of casein kinase 2 and spleen tyrosine kinase to CFTR trafficking and protein kinase A-induced activity. Mol. Cell. Biol. 31, 4392-4404. doi: 10.1128/MCB.05517-11
56. Manning, G., Whyte, D. B., Martinez, R., Hunter, T., and Sudarsanam, S. (2002). The protein kinase complement of the human genome. Science 298, 1912-1934. doi: 10.1126/science.1075762
57. Manser, C., Guillot, F., Vagnoni, A., Davies, J., Lau, K. F., Mcloughlin, D. M., et al. (2012). Lemur tyrosine kinase-2 signalling regulates kinesin-1 light chain-2 phosphorylation and binding of Smad2 cargo. Oncogene 31, 2773-2782. doi: 10.1038/onc.2011.437
58. Marchler-Bauer, A., Anderson, J. B., Deweese-Scott, C., Fedorova, N. D., Geer, L. Y., He, S., et al. (2003). CDD: a curated Entrez database of conserved domain alignments. Nucleic Acids Res. 31, 383-387. doi: 10.1093/nar/gkg087
59. Marchler-Bauer, A., Zheng, C., Chitsaz, F., Derbyshire, M. K., Geer, L. Y., Geer, R. C., et al. (2013). CDD: conserved domains and protein three-dimensional structure. Nucleic Acids Res. 41, D348-D352. doi: 10.1093/nar/gks1243
60. Meacham, G. C., Lu, Z., King, S., Sorscher, E., Tousson, A., and Cyr, D. M. (1999). The Hdj-2/Hsc70 chaperone pair facilitates early steps in CFTR biogenesis. EMBO J. 18, 1492-1505. doi: 10.1093/emboj/18.6.1492
61. Meggio, F., and Pinna, L. A. (2003). One-thousand-and-one substrates of protein kinase CK2? FASEB J. 17, 349-368. doi: 10.1096/fj.02-0473rev
62. Mendes, A. I., Matos, P., Moniz, S., Luz, S., Amaral, M. D., Farinha, C. M., et al. (2011). Antagonistic regulation of CFTR cell surface expression by protein kinases WNK4 and spleen tyrosine kinase. Mol. Cell. Biol. 31, 4076-4086. doi: 10.1128/MCB.05152-11
63. Mendes, A. I., Matos, P., Moniz, S., Luz, S., Amaral, M. D., Farinha, C. M., et al. (2011). Antagonistic regulation of CFTR cell surface expression by protein kinases WNK4 and spleen tyrosine kinase. Mol. Cell. Biol. 31, 4076-4086. doi: 10.1128/MCB.05152-11
64. Mendes, A. I., Matos, P., Moniz, S., Luz, S., Amaral, M. D., Farinha, C. M., et al. (2011). Antagonistic regulation of CFTR cell surface expression by protein kinases WNK4 and spleen tyrosine kinase. Mol. Cell. Biol. 31, 4076-4086. doi: 10.1128/MCB.05152-11
65. Mendes, A. I., Matos, P., Moniz, S., Luz, S., Amaral, M. D., Farinha, C. M., et al. (2011). Antagonistic regulation of CFTR cell surface expression by protein kinases WNK4 and spleen tyrosine kinase. Mol. Cell. Biol. 31, 4076-4086. doi: 10.1128/MCB.05152-11
66. Mócsai, A., Ruland, J., and Tybulewicz, V. L. (2010). The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat. Rev. Immunol. 10, 387-402. doi: 10.1038/nri2765
67. Molinski, S., Eckford, P. D., Pasyk, S., Ahmadi, S., Chin, S., and Bear, C. E. (2012). Functional rescue of F508del-CFTR using small molecule correctors. Front. Pharmacol. 3:160. doi: 10.3389/fphar.2012.00160
68. Moniz, S., Sousa, M., Moraes, B. J., Mendes, A. I., Palma, M., Barreto, C., et al. (2013). HGF stimulation of Rac1 signaling enhances pharmacological correction of the most prevalent cystic fibrosis mutant F508del-CFTR. ACS Chem. Biol. 8, 432-442. doi: 10.1021/cb300484r
69. Nixon, A., Jia, Y., White, C., and Bradbury, N. A. (2013). Determination of the membrane topology of lemur tyrosine kinase 2 (LMTK2) by fluorescence protease protection. Am. J. Physiol. Cell Physiol. 304, C164-C169. doi: 10.1152/ajpcell.00288.2012
70. Nixon, L. S., Yung, B., Bell, S. C., Elborn, J. S., and Shale, D. J. (1998). Circulating immunoreactive interleukin-6 in cystic fibrosis. Am. J. Respir. Crit. Care Med. 157, 1764-1769. doi: 10.1164/ajrccm.157.6.9704086
71. Pagano, M. A., Arrigoni, G., Marin, O., Sarno, S., Meggio, F., Treharne, K. J., et al. (2008). Modulation of protein kinase CK2 activity by fragments of CFTR encompassing F508 may reflect functional links with cystic fibrosis pathogenesis. Biochemistry 47, 7925-7936. doi: 10.1021/bi800316z
72. Pagano, M. A., Marin, O., Cozza, G., Sarno, S., Meggio, F., Treharne, K. J., et al. (2010). Cystic fibrosis transmembrane regulator fragments with the Phe508 deletion exert a dual allosteric control over the master kinase CK2. Biochem. J. 426, 19-29. doi: 10.1042/BJ20090813
73. Pasyk, S., Molinski, S., Ahmadi, S., Ramjeesingh, M., Huan, L. J., Chin, S., et al. (2015). The major cystic fibrosis causing mutation exhibits defective propensity for phosphorylation. Proteomics 15, 447-461. doi: 10.1002/pmic.201400218
74. Pelkmans, L., Fava, E., Grabner, H., Hannus, M., Habermann, B., Krausz, E., et al. (2005). Genome-wide analysis of human kinases in clathrin- and caveolae/raft-mediated endocytosis. Nature 436, 78-86. doi: 10.1038/nature03571
75. Rab, A., Rowe, S. M., Raju, S. V., Bebok, Z., Matalon, S., and Collawn, J. F. (2013). Cigarette smoke and CFTR: implications in the pathogenesis of COPD. Am. J. Physiol. Lung Cell. Mol. Physiol. 305, L530-L541. doi: 10.1152/ajplung.00039.2013
76. Rattray, M. (2012). New insights on regulation of LMTK2, a membrane kinase integrating pathways central to neurodegeneration. J. Neurochem. 121, 327-328. doi: 10.1111/j.1471-4159.2012.07654.x
77. Ring, A. M., Cheng, S. X., Leng, Q., Kahle, K. T., Rinehart, J., Lalioti, M. D., et al. (2007). WNK4 regulates activity of the epithelial Na+ channel in vitro and in vivo. Proc. Natl. Acad. Sci. U.S.A. 104, 4020-4024. doi: 10.1073/pnas.0611727104
78. Riordan, J. R. (2008). CFTR function and prospects for therapy. Annu. Rev. Biochem. 77, 701-726. doi: 10.1146/annurev.biochem.75.103004.142532
79. Scott, G. K., Fei, H., Thomas, L., Medigeshi, G. R., and Thomas, G. (2006). A PACS-1, GGA3 and CK2 complex regulates CI-MPR trafficking. EMBO J. 25, 4423-4435. doi: 10.1038/sj.emboj.7601336
80. Seo, J. S., Ju, Y. S., Lee, W. C., Shin, J. Y., Lee, J. K., Bleazard, T., et al. (2012). The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res. 22, 2109-2119. doi: 10.1101/gr.145144.112
81. Serres, M., Filhol, O., Lickert, H., Grangeasse, C., Chambaz, E. M., Stappert, J., et al. (2000). The disruption of adherens junctions is associated with a decrease of E-cadherin phosphorylation by protein kinase CK2. Exp. Cell Res. 257, 255-264. doi: 10.1006/excr.2000.4895
82. Sharma, M., Pampinella, F., Nemes, C., Benharouga, M., So, J., Du, K., et al. (2004). Misfolding diverts CFTR from recycling to degradation: quality control at early endosomes. J. Cell Biol. 164, 923-933. doi: 10.1083/jcb.200312018
83. Sheppard, D. N., Rich, D. P., Ostedgaard, L. S., Gregory, R. J., Smith, A. E., and Welsh, M. J. (1993). Mutations in CFTR associated with mild-disease-form Cl- channels with altered pore properties. Nature 362, 160-164. doi: 10.1038/362160a0
84. Sosnay, P. R., Siklosi, K. R., Van Goor, F., Kaniecki, K., Yu, H., Sharma, N., et al. (2013). Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat. Genet. 45, 1160-1167. doi: 10.1038/ng.2745
85. Stephens, D. J., and Banting, G. (1997). Insulin dependent tyrosine phosphorylation of the tyrosine internalisation motif of TGN38 creates a specific SH2 domain binding site. FEBS Lett. 416, 27-29. doi: 10.1016/S0014-5793(97)01165-4
86. Stockli, J., Honing, S., and Rohrer, J. (2004). The acidic cluster of the CK2 site of the cation-dependent mannose 6-phosphate receptor (CD-MPR) but not its phosphorylation is required for GGA1 and AP-1 binding. J. Biol. Chem. 279, 23542-23549. doi: 10.1074/jbc.M313525200
87. Subramanya, A. R., Liu, J., Ellison, D. H., Wade, J. B., and Welling, P. A. (2009). WNK4 diverts the thiazide-sensitive NaCl cotransporter to the lysosome and stimulates AP-3 interaction. J. Biol. Chem. 284, 18471-18480. doi: 10.1074/jbc.M109.008185
88. Swiatecka-Urban, A., Boyd, C., Coutermarsh, B., Karlson, K. H., Barnaby, R., Aschenbrenner, L., et al. (2004). Myosin VI regulates endocytosis of the cystic fibrosis transmembrane conductance regulator. J. Biol. Chem. 279, 38025-38031. doi: 10.1074/jbc.M403141200
89. Swiatecka-Urban, A., Brown, A., Moreau-Marquis, S., Renuka, J., Coutermarsh, B., Barnaby, R., et al. (2005). The short apical membrane half-life of rescued {Delta}F508-cystic fibrosis transmembrane conductance regulator (CFTR) results from accelerated endocytosis of {Delta}F508-CFTR in polarized human airway epithelial cells. J. Biol. Chem. 280, 36762-36772. doi: 10.1074/jbc.M508944200
90. Tosoni, K., Stobbart, M., Cassidy, D. M., Venerando, A., Pagano, M. A., Luz, S., et al. (2013). CFTR mutations altering CFTR fragmentation. Biochem. J. 449, 295-305. doi: 10.1042/BJ20121240
91. Treharne, K. J., Xu, Z., Chen, J. H., Best, O. G., Cassidy, D. M., Gruenert, D. C., et al. (2009). Inhibition of protein kinase CK2 closes the CFTR Cl channel, but has no effect on the cystic fibrosis mutant deltaF508-CFTR. Cell. Physiol. Biochem. 24, 347-360. doi: 10.1159/000257427
92. Tsai, L. H., Delalle, I., Caviness, V. S. Jr., Chae, T., and Harlow, E. (1994). p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371, 419-423. doi: 10.1038/371419a0
93. Ulanova, M., Puttagunta, L., Marcet-Palacios, M., Duszyk, M., Steinhoff, U., Duta, F., et al. (2005). Syk tyrosine kinase participates in beta1-integrin signaling and inflammatory responses in airway epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 288, L497-L507. doi: 10.1152/ajplung.00246.2004
94. Van Goor, F., Hadida, S., Grootenhuis, P. D., Burton, B., Stack, J. H., Straley, K. S., et al. (2011). Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc. Natl. Acad. Sci. U.S.A. 108, 18843-18848. doi: 10.1073/pnas.1105787108
95. Van Goor, F., Yu, H., Burton, B., and Hoffman, B. J. (2014). Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J. Cyst. Fibros. 13, 29-36. doi: 10.1016/j.jcf.2013.06.008
96. Venerando, A., Franchin, C., Cant, N., Cozza, G., Pagano, M. A., Tosoni, K., et al. (2013). Detection of phospho-sites generated by protein kinase CK2 in CFTR: mechanistic aspects of Thr1471 phosphorylation. PLoS ONE 8:e74232. doi: 10.1371/journal.pone.0074232
97. Venerando, A., Pagano, M. A., Tosoni, K., Meggio, F., Cassidy, D., Stobbart, M., et al. (2011). Understanding protein kinase CK2 mis-regulation upon F508del CFTR expression. Naunyn-Schmiedebergs Arch. Pharmacol. 384, 473-488. doi: 10.1007/s00210-011-0650-x
98. Veríssimo, F., and Jordan, P. (2001). WNK kinases, a novel protein kinase subfamily in multi-cellular organisms. Oncogene 20, 5562-5569. doi: 10.1038/sj.onc.1204726
99. Wang, H., and Brautigan, D. L. (2002). A novel transmembrane Ser/Thr kinase complexes with protein phosphatase-1 and inhibitor-2. J. Biol. Chem. 277, 49605-49612. doi: 10.1074/jbc.M209335200
100. Wang, H., and Brautigan, D. L. (2006). Peptide microarray analysis of substrate specificity of the transmembrane Ser/Thr kinase KPI-2 reveals reactivity with cystic fibrosis transmembrane conductance regulator and phosphorylase. Mol. Cell. Proteomics 5, 2124-2130. doi: 10.1074/mcp.M600188-MCP200
101. Wang, W., and Linsdell, P. (2012). Conformational change opening the CFTR chloride channel pore coupled to ATP-dependent gating. Biochim. Biophys. Acta 1818, 851-860. doi: 10.1016/j.bbamem.2011.12.025
102. Wilkinson, D. J., Strong, T. V., Mansoura, M. K., Wood, D. L., Smith, S. S., Collins, F. S., et al. (1997). CFTR activation: additive effects of stimulatory and inhibitory phosphorylation sites in the R domain. Am. J. Physiol. 273, L127-133.
103. Wilson, F. H., Disse-Nicodeme, S., Choate, K. A., Ishikawa, K., Nelson-Williams, C., Desitter, I., et al. (2001). Human hypertension caused by mutations in WNK kinases. Science 293, 1107-1112. doi: 10.1126/science.1062844
104. Yang, C. L., Liu, X., Paliege, A., Zhu, X., Bachmann, S., Dawson, D. C., et al. (2007). WNK1 and WNK4 modulate CFTR activity. Biochem. Biophys. Res. Commun. 353, 535-540. doi: 10.1016/j.bbrc.2006.11.151
105. Yu, L., Cai, H., Yue, Q., Alli, A. A., Wang, D., Al-Khalili, O., et al. (2013). WNK4 inhibition of ENaC is independent of Nedd4-2-mediated ENaC ubiquitination. Am. J. Physiol. Renal Physiol. 305, F31-F41. doi: 10.1152/ajprenal.00652.2012
106. Zhuang, J., Zhang, X., Wang, D., Li, J., Zhou, B., Shi, Z., et al. (2011). WNK4 kinase inhibits Maxi K channel activity by a kinase-dependent mechanism. Am. J. Physiol. Renal Physiol. 301, F410-F419. doi: 10.1152/ajprenal.00518.2010
107. Zielenski, J. (2000). Genotype and phenotype in cystic fibrosis. Respiration 67, 117-133. doi: 10.1159/000029497