Open Access

The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review)

  • Authors:
    • Fatima Ardito
    • Michele Giuliani
    • Donatella Perrone
    • Giuseppe Troiano
    • Lorenzo Lo Muzio
  • View Affiliations

  • Published online on: June 22, 2017     https://doi.org/10.3892/ijmm.2017.3036
  • Pages: 271-280
  • Copyright: © Ardito et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Protein phosphorylation is an impo­rtant cellular regulatory mechanism as many enzymes and receptors are activated/deactivated by phosphorylation and dephosphorylation events, by means of kinases and phosph­atases. In particular, the protein kinases are responsible for cellular transduction signaling and their hyperactivity, malfunction or overexpression can be found in several diseases, mostly tumors. Therefore, it is evident that the use of kinase inhibitors can be valuable for the treatment of cancer. In this review, we discuss the mechanism of action of phosphorylation, with particular attention to the importance of phosphorylation under physiological and pathological conditions. We also discuss the possibility of using kinase inhibitors in the treatment of tumors.

References

1 

Li X, Wilmanns M, Thornton J and Köhn M: Elucidating human phosphatase-substrate networks. Sci Signal. 6:rs102013. View Article : Google Scholar : PubMed/NCBI

2 

Sacco F, Perfetto L, Castagnoli L and Cesareni G: The human phosphatase interactome: an intricate family portrait. FEBS Lett. 586:2732–2739. 2012. View Article : Google Scholar : PubMed/NCBI

3 

Alberts B, Johnson A, Lewis J, Raff M, Roberts K and Walter P: Molecular Biology of the Cell. Anderson M and Granum S: 5th edition. Garland Science; New York, NY: pp. 1752007

4 

Hunter T: Why nature chose phosphate to modify proteins. Philos Trans R Soc Lond B Biol Sci. 367:2513–2516. 2009. View Article : Google Scholar

5 

Fukami Y and Lipmann F: Reversal of Rous sarcoma-specific immunoglobulin phosphorylation on tyrosine (ADP as phosphate acceptor) catalyzed by the src gene kinase. Proc Natl Acad Sci USA. 80:1872–1876. 1983. View Article : Google Scholar : PubMed/NCBI

6 

Kole HK, Abdel-Ghany M and Racker E: Specific dephosphorylation of phosphoproteins by protein-serine and -tyrosine kinases. Proc Natl Acad Sci USA. 85:5849–5853. 1988. View Article : Google Scholar : PubMed/NCBI

7 

Roskoski R Jr: ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res. 66:105–143. 2012. View Article : Google Scholar : PubMed/NCBI

8 

Schwartz PA and Murray BW: Protein kinase biochemistry and drug discovery. Bioorg Chem. 39:192–210. 2011. View Article : Google Scholar : PubMed/NCBI

9 

Nishi H, Shaytan A and Panchenko AR: Physicochemical mechanisms of protein regulation by phosphorylation. Front Genet. 5:2702014. View Article : Google Scholar : PubMed/NCBI

10 

McCance KL and Huether SE: Pathophysiology: The Biologic Basis for Disease in Adults and Children. Brashers VL and Rote NS: 7th edition. Elsevier; 2014

11 

Hornberg JJ, Bruggeman FJ, Binder B, Geest CR, de Vaate AJ, Lankelma J, Heinrich R and Westerhoff HV: Principles behind the multifarious control of signal transduction. ERK phosphorylation and kinase/phosphatase control. FEBS J. 272:244–258. 2005. View Article : Google Scholar : PubMed/NCBI

12 

Tonks NK: Protein tyrosine phosphatases: from genes, to function, to disease. Nat Rev Mol Cell Biol. 7:833–846. 2006. View Article : Google Scholar : PubMed/NCBI

13 

Heinrich R, Neel BG and Rapoport TA: Mathematical models of protein kinase signal transduction. Mol Cell. 9:957–970. 2002. View Article : Google Scholar : PubMed/NCBI

14 

Liberti S, Sacco F, Calderone A, Perfetto L, Iannuccelli M, Panni S, Santonico E, Palma A, Nardozza AP, Castagnoli L, et al: HuPho: the human phosphatase portal. FEBS J. 280:379–387. 2013. View Article : Google Scholar

15 

Hatzihristidis T, Liu S, Pryszcz L, Hutchins AP, Gabaldón T, Tremblay ML and Miranda-Saavedra D: PTP-central: a comprehensive resource of protein tyrosine phosphatases in eukaryotic genomes. Methods. 65:156–164. 2014. View Article : Google Scholar

16 

Miller ML, Jensen LJ, Diella F, Jørgensen C, Tinti M, Li L, Hsiung M, Parker SA, Bordeaux J, Sicheritz-Ponten T, et al: Linear motif atlas for phosphorylation-dependent signaling. Sci Signal. 1:–ra2. 2008. View Article : Google Scholar : PubMed/NCBI

17 

Hunter T: Tyrosine phosphorylation: thirty years and counting. Curr Opin Cell Biol. 21:140–146. 2009. View Article : Google Scholar : PubMed/NCBI

18 

Capra M, Nuciforo PG, Confalonieri S, Quarto M, Bianchi M, Nebuloni M, Boldorini R, Pallotti F, Viale G, Gishizky ML, et al: Frequent alterations in the expression of serine/threonine kinases in human cancers. Cancer Res. 66:8147–8154. 2006. View Article : Google Scholar : PubMed/NCBI

19 

Jin J and Pawson T: Modular evolution of phosphorylation-based signalling systems. Philos Trans R Soc Lond B Biol Sci. 367:2540–2555. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Pearce LR, Komander D and Alessi DR: The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol. 11:9–22. 2010. View Article : Google Scholar

21 

Wayman GA, Tokumitsu H, Davare MA and Soderling TR: Analysis of CaM-kinase signaling in cells. Cell Calcium. 50:1–8. 2011. View Article : Google Scholar : PubMed/NCBI

22 

Eide EJ and Virshup DM: Casein kinase I: another cog in the circadian clockworks. Chronobiol Int. 18:389–398. 2001. View Article : Google Scholar : PubMed/NCBI

23 

Sundaram MV: RTK/Ras/MAPK signaling. WormBook: pp. 1–19. 2006, View Article : Google Scholar

24 

Cohen P and Goedert M: GSK3 inhibitors: development and therapeutic potential. Nat Rev Drug Discov. 3:479–487. 2004. View Article : Google Scholar : PubMed/NCBI

25 

Moeslein FM, Myers MP and Landreth GE: The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. J Biol Chem. 274:26697–26704. 1999. View Article : Google Scholar : PubMed/NCBI

26 

Müller-Taubenberger A, Ishikawa-Ankerhold HC, Kastner PM, Burghardt E and Gerisch G: The STE group kinase SepA controls cleavage furrow formation in Dictyostelium. Cell Motil Cytoskeleton. 66:929–939. 2009. View Article : Google Scholar : PubMed/NCBI

27 

Abdi AI, Carvalho TG, Wilkes JM and Doerig C: A secreted Plasmodium falciparum kinase reveals a signature motif for classification of tyrosine kinase-like kinases. Microbiology. 159:2533–2547. 2013. View Article : Google Scholar : PubMed/NCBI

28 

Barford D: Molecular mechanisms of the protein serine/thre-onine phosphatases. Trends Biochem Sci. 21:407–412. 1996. View Article : Google Scholar : PubMed/NCBI

29 

Zhang ZY: Protein tyrosine phosphatases: structure and function, substrate specificity, and inhibitor development. Annu Rev Pharmacol Toxicol. 42:209–234. 2002. View Article : Google Scholar : PubMed/NCBI

30 

Mackintosh C: Protein Phosphorylation: A Practical Approach. Hardie GD: IRL Press; New York, NY: pp. 3281993

31 

Thingholm TE, Larsen MR, Ingrell CR, Kassem M and Jensen ON: TiO(2)-based phosphoproteomic analysis of the plasma membrane and the effects of phosphatase inhibitor treatment. J Proteome Res. 7:3304–3313. 2008. View Article : Google Scholar : PubMed/NCBI

32 

Stern DF: Phosphoproteomics for oncology discovery and treatment. Expert Opin Ther Targets. 9:851–860. 2005. View Article : Google Scholar : PubMed/NCBI

33 

Liu Y and Chance MR: Integrating phosphoproteomics in systems biology. Comput Struct Biotechnol J. 10:90–97. 2014. View Article : Google Scholar : PubMed/NCBI

34 

Moorhead GB, De Wever V, Templeton G and Kerk D: Evolution of protein phosphatases in plants and animals. Biochem J. 417:401–409. 2009. View Article : Google Scholar

35 

Das AK, Helps NR, Cohen PT and Barford D: Crystal structure of the protein serine/threonine phosphatase 2C at 2.0 A resolution. EMBO J. 15:6798–6809. 1996.PubMed/NCBI

36 

Shi Y: Serine/threonine phosphatases: mechanism through structure. Cell. 139:468–484. 2009. View Article : Google Scholar : PubMed/NCBI

37 

Virshup DM and Shenolikar S: From promiscuity to precision: protein phosphatases get a makeover. Mol Cell. 33:537–545. 2009. View Article : Google Scholar : PubMed/NCBI

38 

Guan KL and Dixon JE: Evidence for protein-tyrosine-phosphatase catalysis proceeding via a cysteine-phosphate intermediate. J Biol Chem. 266:17026–17030. 1991.PubMed/NCBI

39 

Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A, Godzik A, Hunter T, Dixon J and Mustelin T: Protein tyrosine phosphatases in the human genome. Cell. 117:699–711. 2004. View Article : Google Scholar : PubMed/NCBI

40 

Tonks NK and Neel BG: Combinatorial control of the specificity of protein tyrosine phosphatases. Curr Opin Cell Biol. 13:182–195. 2001. View Article : Google Scholar : PubMed/NCBI

41 

Wrighton KH, Willis D, Long J, Liu F, Lin X and Feng XH: Small C-terminal domain phosphatases dephosphorylate the regulatory linker regions of Smad2 and Smad3 to enhance transforming growth factor-beta signaling. J Biol Chem. 281:38365–38375. 2006. View Article : Google Scholar : PubMed/NCBI

42 

Archambault J, Pan G, Dahmus GK, Cartier M, Marshall N, Zhang S, Dahmus ME and Greenblatt J: FCP1, the RAP74-interacting subunit of a human protein phosphatase that dephosphorylates the carboxyl-terminal domain of RNA polymerase IIO. J Biol Chem. 273:27593–27601. 1998. View Article : Google Scholar : PubMed/NCBI

43 

Salton SR: Teaching resources. Protein phosphatases. Sci STKE. 2005:tr82005.PubMed/NCBI

44 

Tootle TL, Silver SJ, Davies EL, Newman V, Latek RR, Mills IA, Selengut JD, Parlikar BE and Rebay I: The transcription factor eyes absent is a protein tyrosine phosphatase. Nature. 426:299–302. 2003. View Article : Google Scholar : PubMed/NCBI

45 

Gentry MS, Dixon JE and Worby CA: Lafora disease: insights into neurodegeneration from plant metabolism. Trends Biochem Sci. 34:628–639. 2009. View Article : Google Scholar : PubMed/NCBI

46 

Gentry MS, Dowen RH III, Worby CA, Mattoo S, Ecker JR and Dixon JE: The phosphatase laforin crosses evolutionary boundaries and links carbohydrate metabolism to neuronal disease. J Cell Biol. 178:477–488. 2007. View Article : Google Scholar : PubMed/NCBI

47 

Niittylä T, Comparot-Moss S, Lue WL, Messerli G, Trevisan M, Seymour MD, Gatehouse JA, Villadsen D, Smith SM, Chen J, et al: Similar protein phosphatases control starch metabolism in plants and glycogen metabolism in mammals. J Biol Chem. 281:11815–11818. 2006. View Article : Google Scholar : PubMed/NCBI

48 

Case N, Thomas J, Sen B, Styner M, Xie Z, Galior K and Rubin J: Mechanical regulation of glycogen synthase kinase 3β (GSK3β) in mesenchymal stem cells is dependent on Akt protein serine 473 phosphorylation via mTORC2 protein. J Biol Chem. 286:39450–39456. 2011. View Article : Google Scholar : PubMed/NCBI

49 

Cole PA, Shen K, Qiao Y and Wang D: Protein tyrosine kinases Src and Csk: a tail's tale. Curr Opin Chem Biol. 7:580–585. 2003. View Article : Google Scholar : PubMed/NCBI

50 

Nishi H, Hashimoto K and Panchenko AR: Phosphorylation in protein-protein binding: effect on stability and function. Structure. 19:1807–1815. 2011. View Article : Google Scholar : PubMed/NCBI

51 

Nishi H, Fong JH, Chang C, Teichmann SA and Panchenko AR: Regulation of protein-protein binding by coupling between phosphorylation and intrinsic disorder: analysis of human protein complexes. Mol Biosyst. 9:1620–1626. 2013. View Article : Google Scholar : PubMed/NCBI

52 

Harita Y, Kurihara H, Kosako H, Tezuka T, Sekine T, Igarashi T and Hattori S: Neph1, a component of the kidney slit diaphragm, is tyrosine-phosphorylated by the Src family tyrosine kinase and modulates intracellular signaling by binding to Grb2. J Biol Chem. 283:9177–9186. 2008. View Article : Google Scholar : PubMed/NCBI

53 

Kuwahara H, Nishizaki M and Kanazawa H: Nuclear localization signal and phosphorylation of Serine350 specify intracellular localization of DRAK2. J Biochem. 143:349–358. 2008. View Article : Google Scholar

54 

Shimazaki Y, Nishiki T, Omori A, Sekiguchi M, Kamata Y, Kozaki S and Takahashi M: Phosphorylation of 25-kDa synaptosome-associated protein. Possible involvement in protein kinase C-mediated regulation of neurotransmitter release. J Biol Chem. 271:14548–14553. 1996. View Article : Google Scholar : PubMed/NCBI

55 

Kataoka M, Kuwahara R, Iwasaki S, Shoji-Kasai Y and Takahashi M: Nerve growth factor-induced phosphorylation of SNAP-25 in PC12 cells: a possible involvement in the regulation of SNAP-25 localization. J Neurochem. 74:2058–2066. 2000. View Article : Google Scholar : PubMed/NCBI

56 

Rosen OM and Erlichman J: Reversible autophosphorylation of a cyclic 3′:5′-AMP-dependent protein kinase from bovine cardiac muscle. J Biol Chem. 250:7788–7794. 1975.PubMed/NCBI

57 

Hunter T: The age of crosstalk: phosphorylation, ubiquitination, and beyond. Mol Cell. 28:730–738. 2007. View Article : Google Scholar : PubMed/NCBI

58 

Xu X, Sarikas A, Dias-Santagata DC, Dolios G, Lafontant PJ, Tsai SC, Zhu W, Nakajima H, Nakajima HO, Field LJ, et al: The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for ubiquitin-dependent degradation. Mol Cell. 30:403–414. 2008. View Article : Google Scholar : PubMed/NCBI

59 

Pende M, Um SH, Mieulet V, Sticker M, Goss VL, Mestan J, Mueller M, Fumagalli S, Kozma SC and Thomas G: S6K1(−/−)/S6K2(−/−) mice exhibit perinatal lethality and rapamycin-sensitive 5′-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol Cell Biol. 24:3112–3124. 2004. View Article : Google Scholar : PubMed/NCBI

60 

Ferrer I, Blanco R, Carmona M, Puig B, Domínguez I and Viñals F: Active, phosphorylation-dependent MAP kinases, MAPK/ERK, SAPK/JNK and p38, and specific transcription factor substrates are differentially expressed following systemic administration of kainic acid to the adult rat. Acta Neuropathol. 103:391–407. 2002. View Article : Google Scholar : PubMed/NCBI

61 

Chang L and Karin M: Mammalian MAP kinase signalling cascades. Nature. 410:37–40. 2001. View Article : Google Scholar : PubMed/NCBI

62 

Darnell JE Jr, Kerr IM and Stark GR: Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 264:1415–1421. 1994. View Article : Google Scholar : PubMed/NCBI

63 

Greenlund AC, Farrar MA, Viviano BL and Schreiber RD: Ligand-induced IFN gamma receptor tyrosine phosphorylation couples the receptor to its signal transduction system (p91). EMBO J. 13:1591–1600. 1994.PubMed/NCBI

64 

Igarashi K, Garotta G, Ozmen L, Ziemiecki A, Wilks AF, Harpur AG, Larner AC and Finbloom DS: Interferon-gamma induces tyrosine phosphorylation of interferon-gamma receptor and regulated association of protein tyrosine kinases, Jak1 and Jak2, with its receptor. J Biol Chem. 269:14333–14336. 1994.PubMed/NCBI

65 

Decker T and Kovarik P: Serine phosphorylation of STATs. Oncogene. 19:2628–2637. 2000. View Article : Google Scholar : PubMed/NCBI

66 

Liu Z, Wang Y and Xue Y: Phosphoproteomics-based network medicine. FEBS J. 280:5696–5704. 2013. View Article : Google Scholar : PubMed/NCBI

67 

Hirschi A, Cecchini M, Steinhardt RC, Schamber MR, Dick FA and Rubin SM: An overlapping kinase and phosphatase docking site regulates activity of the retinoblastoma protein. Nat Struct Mol Biol. 17:1051–1057. 2010. View Article : Google Scholar : PubMed/NCBI

68 

Salazar C and Höfer T: Competition effects shape the response sensitivity and kinetics of phosphorylation cycles in cell signaling. Ann NY Acad Sci. 1091:517–530. 2006. View Article : Google Scholar

69 

Lienhard GE: Non-functional phosphorylations? Trends Biochem Sci. 33:351–352. 2008. View Article : Google Scholar : PubMed/NCBI

70 

Landry CR, Levy ED and Michnick SW: Weak functional constraints on phosphoproteomes. Trends Genet. 25:193–197. 2009. View Article : Google Scholar : PubMed/NCBI

71 

Levy ED, Michnick SW and Landry CR: Protein abundance is key to distinguish promiscuous from functional phosphorylation based on evolutionary information. Philos Trans R Soc Lond B Biol Sci. 367:2594–2606. 2012. View Article : Google Scholar : PubMed/NCBI

72 

Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P and Mann M: Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell. 127:635–648. 2006. View Article : Google Scholar : PubMed/NCBI

73 

Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y, et al: Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 131:1190–1203. 2007. View Article : Google Scholar : PubMed/NCBI

74 

Linding R, Jensen LJ, Ostheimer GJ, van Vugt MA, Jørgensen C, Miron IM, Diella F, Colwill K, Taylor L, Elder K, et al: Systematic discovery of in vivo phosphorylation networks. Cell. 129:1415–1426. 2007. View Article : Google Scholar : PubMed/NCBI

75 

Newman RH, Hu J, Rho HS, Xie Z, Woodard C, Neiswinger J, Cooper C, Shirley M, Clark HM, Hu S, et al: Construction of human activity-based phosphorylation networks. Mol Syst Biol. 9:6552013. View Article : Google Scholar : PubMed/NCBI

76 

Drake JM, Graham NA, Stoyanova T, Sedghi A, Goldstein AS, Cai H, Smith DA, Zhang H, Komisopoulou E, Huang J, et al: Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression. Proc Natl Acad Sci USA. 109:1643–1648. 2012. View Article : Google Scholar : PubMed/NCBI

77 

Harsha HC and Pandey A: Phosphoproteomics in cancer. Mol Oncol. 4:482–495. 2010. View Article : Google Scholar : PubMed/NCBI

78 

Hanahan D and Weinberg RA: Hallmarks of cancer: the next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI

79 

Hynes NE and MacDonald G: ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol. 21:177–184. 2009. View Article : Google Scholar : PubMed/NCBI

80 

Sharma A, Tan TH, Cheetham G, Scott HS and Brown MP: Rare and novel epidermal growth factor receptor mutations in non-small-cell lung cancer and lack of clinical response to gefitinib in two cases. J Thorac Oncol. 7:941–942. 2012. View Article : Google Scholar : PubMed/NCBI

81 

Vogelstein B and Kinzler KW: Cancer genes and the pathways they control. Nat Med. 10:789–799. 2004. View Article : Google Scholar : PubMed/NCBI

82 

Petricoin EF, Zoon KC, Kohn EC, Barrett JC and Liotta LA: Clinical proteomics: translating benchside promise into bedside reality. Nat Rev Drug Discov. 1:683–695. 2002. View Article : Google Scholar : PubMed/NCBI

83 

Jones PA and Baylin SB: The fundamental role of epigenetic events in cancer. Nat Rev Genet. 3:415–428. 2002.PubMed/NCBI

84 

Hanahan D and Weinberg RA: The hallmarks of cancer. Cell. 100:57–70. 2000. View Article : Google Scholar : PubMed/NCBI

85 

Tarrant MK and Cole PA: The chemical biology of protein phosphorylation. Annu Rev Biochem. 78:797–825. 2009. View Article : Google Scholar : PubMed/NCBI

86 

Paul MK and Mukhopadhyay AK: Tyrosine kinase - role and significance in cancer. Int J Med Sci. 1:101–115. 2004. View Article : Google Scholar

87 

Murphree AL and Benedict WF: Retinoblastoma: clues to human oncogenesis. Science. 223:1028–1033. 1984. View Article : Google Scholar : PubMed/NCBI

88 

Stehelin D, Guntaka RV, Varmus HE and Bishop JM: Purification of DNA complementary to nucleotide sequences required for neoplastic transformation of fibroblasts by avian sarcoma viruses. J Mol Biol. 101:349–365. 1976. View Article : Google Scholar : PubMed/NCBI

89 

Hunter T and Cooper JA: Protein-tyrosine kinases. Annu Rev Biochem. 54:897–930. 1985. View Article : Google Scholar : PubMed/NCBI

90 

Sefton BM and Hunter T: From c-src to v-src, or the case of the missing C terminus. Cancer Surv. 5:159–172. 1986.PubMed/NCBI

91 

Sefton BM, Hunter T and Raschke WC: Evidence that the Abelson virus protein functions in vivo as a protein kinase that phosphorylates tyrosine. Proc Natl Acad Sci USA. 78:1552–1556. 1981. View Article : Google Scholar : PubMed/NCBI

92 

Sefton BM, Hunter T, Beemon K and Eckhart W: Evidence that the phosphorylation of tyrosine is essential for cellular transformation by Rous sarcoma virus. Cell. 20:807–816. 1980. View Article : Google Scholar : PubMed/NCBI

93 

Xu W, Doshi A, Lei M, Eck MJ and Harrison SC: Crystal structures of c-Src reveal features of its autoinhibitory mechanism. Mol Cell. 3:629–638. 1999. View Article : Google Scholar : PubMed/NCBI

94 

Young MA, Gonfloni S, Superti-Furga G, Roux B and Kuriyan J: Dynamic coupling between the SH2 and SH3 domains of c-Src and Hck underlies their inactivation by C-terminal tyrosine phosphorylation. Cell. 105:115–126. 2001. View Article : Google Scholar : PubMed/NCBI

95 

Shawver LK, Slamon D and Ullrich A: Smart drugs: tyrosine kinase inhibitors in cancer therapy. Cancer Cell. 1:117–123. 2002. View Article : Google Scholar : PubMed/NCBI

96 

Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A and McGuire WL: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 235:177–182. 1987. View Article : Google Scholar : PubMed/NCBI

97 

Lee CH, Syu SH, Liu KJ, Chu PY, Yang WC, Lin P and Shieh WY: Interleukin-1 beta transactivates epidermal growth factor receptor via the CXCL1-CXCR2 axis in oral cancer. Oncotarget. 6:38866–38880. 2015.PubMed/NCBI

98 

Corless CL, Fletcher JA and Heinrich MC: Biology of gastrointestinal stromal tumors. J Clin Oncol. 22:3813–3825. 2004. View Article : Google Scholar : PubMed/NCBI

99 

Javidi-Sharifi N, Traer E, Martinez J, Gupta A, Taguchi T, Dunlap J, Heinrich MC, Corless CL, Rubin BP, Druker BJ, et al: Crosstalk between KIT and FGFR3 promotes gastrointestinal stromal tumor cell growth and drug resistance. Cancer Res. 75:880–891. 2015. View Article : Google Scholar :

100 

Sharma SV, Bell DW, Settleman J and Haber DA: Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 7:169–181. 2007. View Article : Google Scholar : PubMed/NCBI

101 

Zhu N, Xiao H, Wang LM, Fu S, Zhao C and Huang H: Mutations in tyrosine kinase and tyrosine phosphatase and their relevance to the target therapy in hematologic malignancies. Future Oncol. 11:659–673. 2015. View Article : Google Scholar : PubMed/NCBI

102 

Kraus J, Kraus M, Liu N, Besse L, Bader J, Geurink PP, de Bruin G, Kisselev AF, Overkleeft H and Driessen C: The novel β2-selective proteasome inhibitor LU-102 decreases phosphorylation of I kappa B and induces highly synergistic cytotoxicity in combination with ibrutinib in multiple myeloma cells. Cancer Chemother Pharmacol. 76:383–396. 2015. View Article : Google Scholar : PubMed/NCBI

103 

Jagarlamudi KK, Hansson LO and Eriksson S: Breast and prostate cancer patients differ significantly in their serum thymidine kinase 1 (TK1) specific activities compared with those hematological malignancies and blood donors: implications of using serum TK1 as a biomarker. BMC Cancer. 15:662015. View Article : Google Scholar : PubMed/NCBI

104 

Hou S, Isaji T, Hang Q, Im S, Fukuda T and Gu J: Distinct effects of β1 integrin on cell proliferation and cellular signaling in MDA-MB-231 breast cancer cells. Sci Rep. 6:184302016. View Article : Google Scholar

105 

Paladino D, Yue P, Furuya H, Acoba J, Rosser CJ and Turkson J: A novel nuclear Src and p300 signaling axis controls migratory and invasive behavior in pancreatic cancer. Oncotarget. 7:7253–7267. 2016.

106 

Li Z, Lin P, Gao C, Peng C, Liu S, Gao H, Wang B, Wang J, Niu J and Niu W: Integrin β6 acts as an unfavorable prognostic indicator and promotes cellular malignant behaviors via ERK-ETS1 pathway in pancreatic ductal adenocarcinoma (PDAC). Tumour Biol. 37:5117–5131. 2016. View Article : Google Scholar

107 

Meh raein-Ghom i F, Chu rch DR, Sch reiber CL, Weichmann AM, Basu HS and Wilding G: Inhibitor of p52 NF-κB subunit and androgen receptor (AR) interaction reduces growth of human prostate cancer cells by abrogating nuclear translocation of p52 and phosphorylated AR(ser81). Genes Cancer. 6:428–444. 2015.

108 

Barber TD, Vogelstein B, Kinzler KW and Velculescu VE: Somatic mutations of EGFR in colorectal cancers and glioblastomas. N Engl J Med. 351:28832004. View Article : Google Scholar : PubMed/NCBI

109 

Blume-Jensen P and Hunter T: Oncogenic kinase signalling. Nature. 411:355–365. 2001. View Article : Google Scholar : PubMed/NCBI

110 

Parsons DW, Wang TL, Samuels Y, Bardelli A, Cummins JM, DeLong L, Silliman N, Ptak J, Szabo S, Willson JK, et al: Colorectal cancer: mutations in a signalling pathway. Nature. 436:7922005. View Article : Google Scholar : PubMed/NCBI

111 

Stephens P, Edkins S, Davies H, Greenman C, Cox C, Hunter C, Bignell G, Teague J, Smith R, Stevens C, et al: A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer. Nat Genet. 37:590–592. 2005. View Article : Google Scholar : PubMed/NCBI

112 

Ludwig JA and Weinstein JN: Biomarkers in cancer staging, prognosis and treatment selection. Nat Rev Cancer. 5:845–856. 2005. View Article : Google Scholar : PubMed/NCBI

113 

Rubio-Viqueira B and Hidalgo M: Targeting mTOR for cancer treatment. Adv Exp Med Biol. 587:309–327. 2006. View Article : Google Scholar : PubMed/NCBI

114 

Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ and Abraham RT: Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol. 22:7004–7014. 2002. View Article : Google Scholar : PubMed/NCBI

115 

Dancey JE: Therapeutic targets: MTOR and related pathways. Cancer Biol Ther. 5:1065–1073. 2006. View Article : Google Scholar : PubMed/NCBI

116 

Thomas GV, Tran C, Mellinghoff IK, Welsbie DS, Chan E, Fueger B, Czernin J and Sawyers CL: Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med. 12:122–127. 2006. View Article : Google Scholar

117 

Ahmadian MR: Prospects for anti-ras drugs. Br J Haematol. 116:511–518. 2002. View Article : Google Scholar : PubMed/NCBI

118 

Goodsell DS: The molecular perspective: the ras oncogene. Oncologist. 4:263–264. 1999.PubMed/NCBI

119 

Sawyers CL: Shifting paradigms: the seeds of oncogene addiction. Nat Med. 15:1158–1161. 2009. View Article : Google Scholar : PubMed/NCBI

120 

Hainaut P and Plymoth A: Targeting the hallmarks of cancer: towards a rational approach to next-generation cancer therapy. Curr Opin Oncol. 25:50–51. 2013. View Article : Google Scholar

121 

Gonzalez de Castro D, Clarke PA, Al-Lazikani B and Workman P: Personalized cancer medicine: molecular diagnostics, predictive biomarkers, and drug resistance. Clin Pharmacol Ther. 93:252–259. 2013. View Article : Google Scholar : PubMed/NCBI

122 

Druker BJ: Imatinib mesylate in the treatment of chronic myeloid leukaemia. Expert Opin Pharmacother. 4:963–971. 2003. View Article : Google Scholar : PubMed/NCBI

123 

Stegmeier F, Warmuth M, Sellers WR and Dorsch M: Targeted cancer therapies in the twenty-first century: lessons from imatinib. Clin Pharmacol Ther. 87:543–552. 2010. View Article : Google Scholar : PubMed/NCBI

124 

Bachman KE, Argani P, Samuels Y, Silliman N, Ptak J, Szabo S, Konishi H, Karakas B, Blair BG, Lin C, et al: The IK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther. 3:772–775. 2004. View Article : Google Scholar : PubMed/NCBI

125 

Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, Botero ML, Llonch E, Atzori F, Di Cosimo S, et al: NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 68:8022–8030. 2008. View Article : Google Scholar : PubMed/NCBI

126 

Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, Einhorn E, Herlyn M, Minna J, Nicholson A, et al: BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 62:6997–7000. 2002.PubMed/NCBI

127 

Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, et al BRIM-3 Study Group: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 364:2507–2516. 2011. View Article : Google Scholar : PubMed/NCBI

128 

Young K, Minchom A and Larkin J: BRIM-1, -2 and -3 trials: improved survival with vemurafenib in metastatic melanoma patients with a BRAF(V600E) mutation. Future Oncol. 8:499–507. 2012. View Article : Google Scholar : PubMed/NCBI

129 

Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 361:947–957. 2009. View Article : Google Scholar : PubMed/NCBI

130 

Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, et al: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 304:1497–1500. 2004. View Article : Google Scholar : PubMed/NCBI

131 

Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, et al RECORD-1 Study Group: Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 372:449–456. 2008. View Article : Google Scholar : PubMed/NCBI

132 

Abdurahman A, Anwar J, Turghun A, Niyaz M, Zhang L and Awut I: Epidermal growth factor receptor gene mutation status and its association with clinical characteristics and tumor markers in non-small-cell lung cancer patients in Northwest China. Mol Clin Oncol. 3:847–850. 2015.PubMed/NCBI

133 

Ulivi P, Chiadini E, Dazzi C, Dubini A, Costantini M, Medri L, Puccetti M, Capelli L, Calistri D, Verlicchi A, et al: Nonsquamous, non-small-cell lung cancer patients who carry a double mutation of EGFR, EML4-ALK or KRAS: frequency, clinical-pathological characteristics, and response to therapy. Clin Lung Cancer. 17:384–390. 2016. View Article : Google Scholar

134 

Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, et al: Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 371:1867–1876. 2014. View Article : Google Scholar : PubMed/NCBI

135 

Carvajal-Hausdorf DE, Schalper KA, Pusztai L, Psyrri A, Kalogeras KT, Kotoula V, Fountzilas G and Rimm DL: Measurement of domain-specific HER2 (ERBB2) expression may classify benefit from trastuzumab in breast cancer. J Natl Cancer Inst. 107:djv1362015. View Article : Google Scholar : PubMed/NCBI

136 

Hasskarl J: Sorafenib: targeting multiple tyrosine kinases in cancer. Recent Results Cancer Res. 201:145–164. 2014. View Article : Google Scholar : PubMed/NCBI

137 

Aita Y, Ishii KA, Saito Y, Ikeda T, Kawakami Y, Shimano H, Hara H and Takekoshi K: Sunitinib inhibits catecholamine synthesis and secretion in pheochromocytoma tumor cells by blocking VEGF receptor 2 via PLC-γ-related pathways. Am J Physiol Endocrinol Metab. 303:E1006–E1014. 2012. View Article : Google Scholar : PubMed/NCBI

138 

Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, et al: Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 368:1329–1338. 2006. View Article : Google Scholar : PubMed/NCBI

139 

Czarnecka AM, Solarek W, Kornakiewicz A and Szczylik C: Tyrosine kinase inhibitors target cancer stem cells in renal cell cancer. Oncol Rep. 35:1433–1442. 2016.

140 

Lankheet NA, Huitema AD, Mallo H, Adriaansz S, Haanen JB, Schellens JH, Beijnen JH and Blank CU: The effect of seasonal variation and secretion of sunitinib in sweat on the development of hand-foot syndrome. Eur J Clin Pharmacol. 69:2065–2072. 2013. View Article : Google Scholar : PubMed/NCBI

141 

Axelsson J, Rippe A and Rippe B: mTOR inhibition with temsirolimus causes acute increases in glomerular permeability, but inhibits the dynamic permeability actions of puromycin aminonucleoside. Am J Physiol Renal Physiol. 308:F1056–F1064. 2015. View Article : Google Scholar : PubMed/NCBI

142 

Wan X, Shen N, Mendoza A, Khanna C and Helman LJ: CCI-779 inhibits rhabdomyosarcoma xenograft growth by an antiangiogenic mechanism linked to the targeting of mTOR/Hif-1alpha/VEGF signaling. Neoplasia. 8:394–401. 2006. View Article : Google Scholar : PubMed/NCBI

143 

Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, et al: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 20:719–726. 2002. View Article : Google Scholar : PubMed/NCBI

144 

Cutillas PR: Role of phosphoproteomics in the development of personalized cancer therapies. Proteomics Clin Appl. 9:383–395. 2015. View Article : Google Scholar

145 

Klempner SJ, Myers AP and Cantley LC: What a tangled web we weave: emerging resistance mechanisms to inhibition of the phosphoinositide 3-kinase pathway. Cancer Discov. 3:1345–1354. 2013. View Article : Google Scholar : PubMed/NCBI

146 

Robin X, Creixell P, Radetskaya O, Santini CC, Longden J and Linding R: Personalized network-based treatments in oncology. Clin Pharmacol Ther. 94:646–650. 2013. View Article : Google Scholar : PubMed/NCBI

147 

Elkabets M, Vora S, Juric D, Morse N, Mino-Kenudson M, Muranen T, Tao J, Campos AB, Rodon J, Ibrahim YH, et al: mTORC1 inhibition is required for sensitivity to PI3K110α inhibitors in PIK3CA-mutant breast cancer. Sci Transl Med. 5:196ra992013. View Article : Google Scholar

148 

Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, Davis A, Mongare MM, Gould J, Frederick DT, et al: Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 487:500–504. 2012. View Article : Google Scholar : PubMed/NCBI

149 

Murray BW and Miller N: Durability of kinase-directed therapies - a network perspective on response and resistance. Mol Cancer Ther. 14:1975–1984. 2015. View Article : Google Scholar : PubMed/NCBI

150 

Daub H, Specht K and Ullrich A: Strategies to overcome resistance to targeted protein kinase inhibitors. Nat Rev Drug Discov. 3:1001–1010. 2004. View Article : Google Scholar : PubMed/NCBI

151 

Yoshida T, Zhang G and Haura EB: Targeting epidermal growth factor receptor: central signaling kinase in lung cancer. Biochem Pharmacol. 80:613–623. 2010. View Article : Google Scholar : PubMed/NCBI

152 

Balius TE and Rizzo RC: Quantitative prediction of fold resistance for inhibitors of EGFR. Biochemistry. 48:8435–8448. 2009. View Article : Google Scholar : PubMed/NCBI

153 

Dixit A and Verkhivker GM: Hierarchical modeling of activation mechanisms in the ABL and EGFR kinase domains: thermodynamic and mechanistic catalysts of kinase activation by cancer mutations. PLOS Comput Biol. 5:e10004872009. View Article : Google Scholar : PubMed/NCBI

154 

Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M and Eck MJ: The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA. 105:2070–2075. 2008. View Article : Google Scholar : PubMed/NCBI

155 

Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, Ye Q, Lobo JM, She Y, Osman I, et al: BRAF mutation predicts sensitivity to MEK inhibition. Nature. 439:358–362. 2006. View Article : Google Scholar

156 

Denis MG, Vallée A and Théoleyre S: EGFR T790M resistance mutation in non small-cell lung carcinoma. Clin Chim Acta. 444:81–85. 2015. View Article : Google Scholar : PubMed/NCBI

157 

Niederst MJ and Engelman JA: Bypass mechanisms of resistance to receptor tyrosine kinase inhibition in lung cancer. Sci Signal. 6:re62013. View Article : Google Scholar : PubMed/NCBI

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August 2017
Volume 40 Issue 2

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Online ISSN:1791-244X

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APA
Ardito, F., Giuliani, M., Perrone, D., Troiano, G., & Lo Muzio, L. (2017). The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review). International Journal of Molecular Medicine, 40, 271-280. https://doi.org/10.3892/ijmm.2017.3036
MLA
Ardito, F., Giuliani, M., Perrone, D., Troiano, G., Lo Muzio, L."The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review)". International Journal of Molecular Medicine 40.2 (2017): 271-280.
Chicago
Ardito, F., Giuliani, M., Perrone, D., Troiano, G., Lo Muzio, L."The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review)". International Journal of Molecular Medicine 40, no. 2 (2017): 271-280. https://doi.org/10.3892/ijmm.2017.3036