DOK7V1 influences the malignant phenotype of lung cancer cells through PI3K/AKT/mTOR and FAK/paxillin signaling pathways

  • Authors:
    • Huishan Zhao
    • Gang Chen
    • Lin Ye
    • Hefen Yu
    • Shenglan Li
    • Wen G. Jiang
  • View Affiliations

  • Published online on: November 5, 2018     https://doi.org/10.3892/ijo.2018.4624
  • Pages: 381-389
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Abstract

Downstream of tyrosine kinase 7 transcript variant 1 (DOK7V1) is a docking protein mediating signal transduction between receptors and intracellular downstream molecules. Our previous study indicated that DOK7V1 was decreased in lung cancer and its lower expression was associated with a decreased survival rate. The 5‑year overall survival rate for patients with lung cancer was 20.2 and 18.6% for high and low DOK7 expression, respectively; the 5‑year disease‑free survival rate for patients with lung cancer was 14.3 and 16.9% for high and low DOK7 expression, respectively. DOK7V1 inhibited proliferation and migration, but enhanced adhesion, of lung cancer cells. In the present study, the effect of DOK7V1 and its domains [pleckstrin homology (PH) and phosphotyrosine‑binding (PTB) domain] on the malignant phenotype and associated signaling pathway in lung cancer cells was investigated. The results indicated that truncation of DOK7V1 domains (DOK7V1Δ‑PH and DOK7V1Δ‑PTB) inhibited the proliferation and migration of lung cancer cells which exhibited the same trend as DOK7V1, whereas DOK7V1Δ‑PH and DOK7V1Δ‑PTB exhibited different functions from those of DOK7V1 in cell matrix adhesion. Consistently, DOK7V1 overexpression in lung cancer cells suppressed the phosphoinositide 3‑kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathways, but activated the focal adhesion kinase (FAK)/paxillin signaling pathway. Taken together, these results indicate that DOK7V1 may inhibit proliferation and migration via negatively regulating the PI3K/AKT/mTOR signaling pathway, and increase adhesion by upregulating the FAK/paxillin signaling pathway in lung cancer cells.

References

1 

Siegel RL, Miller KD and Jemal A: Cancer Statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI

2 

Goldstraw P, Ball D, Jett JR, Le Chevalier T, Lim E, Nicholson AG and Shepherd FA: Non-small-cell lung cancer. Lancet. 378:1727–1740. 2011. View Article : Google Scholar : PubMed/NCBI

3 

Yang M, Lewinska M, Fan X, Zhu J and Yuan ZM: PRR14 is a novel activator of the PI3K pathway promoting lung carcinogenesis. Oncogene. 35:5527–5538. 2016. View Article : Google Scholar : PubMed/NCBI

4 

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

5 

Ullrich A and Schlessinger J: Signal transduction by receptors with tyrosine kinase activity. Cell. 61:203–212. 1990. View Article : Google Scholar : PubMed/NCBI

6 

Lemmon MA and Schlessinger J: Cell signaling by receptor tyrosine kinases. Cell. 141:1117–1134. 2010. View Article : Google Scholar : PubMed/NCBI

7 

Berger AH, Niki M, Morotti A, Taylor BS, Socci ND, Viale A, Brennan C, Szoke J, Motoi N, Rothman PB, et al: Identification of DOK genes as lung tumor suppressors. Nat Genet. 42:216–223. 2010. View Article : Google Scholar : PubMed/NCBI

8 

Simister PC and Feller SM: Order and disorder in large multi-site docking proteins of the Gab family–implications for signalling complex formation and inhibitor design strategies. Mol Biosyst. 8:33–46. 2012. View Article : Google Scholar

9 

Jones N and Dumont DJ: Recruitment of Dok-R to the EGF receptor through its PTB domain is required for attenuation of Erk MAP kinase activation. Curr Biol. 9:1057–1060. 1999. View Article : Google Scholar : PubMed/NCBI

10 

Bedirian A, Baldwin C, Abe J, Takano T and Lemay S: Pleckstrin homology and phosphotyrosine-binding domain-dependent membrane association and tyrosine phosphorylation of Dok-4, an inhibitory adapter molecule expressed in epithelial cells. J Biol Chem. 279:19335–19349. 2004. View Article : Google Scholar : PubMed/NCBI

11 

Mashima R, Honda K, Yang Y, Morita Y, Inoue A, Arimura S, Nishina H, Ema H, Nakauchi H, Seed B, et al: Mice lacking Dok-1, Dok-2, and Dok-3 succumb to aggressive histiocytic sarcoma. Lab Invest. 90:1357–1364. 2010. View Article : Google Scholar : PubMed/NCBI

12 

Crowder RJ, Enomoto H, Yang M, Johnson EM Jr and Milbrandt J: Dok-6, a Novel p62 Dok family member, promotes Ret-mediated neurite outgrowth. J Biol Chem. 279:42072–42081. 2004. View Article : Google Scholar : PubMed/NCBI

13 

Grimm J, Sachs M, Britsch S, Di Cesare S, Schwarz-Romond T, Alitalo K and Birchmeier W: Novel p62dok family members, dok-4 and dok-5, are substrates of the c-Ret receptor tyrosine kinase and mediate neuronal differentiation. J Cell Biol. 154:345–354. 2001. View Article : Google Scholar : PubMed/NCBI

14 

Cossins J, Liu WW, Belaya K, Maxwell S, Oldridge M, Lester T, Robb S and Beeson D: The spectrum of mutations that underlie the neuromuscular junction synaptopathy in DOK7 congenital myasthenic syndrome. Hum Mol Genet. 21:3765–3775. 2012. View Article : Google Scholar : PubMed/NCBI

15 

An CH, Kim MS, Yoo NJ and Lee SH: Mutational and expressional analysis of a haploinsufficient tumor suppressor gene DOK2 in gastric and colorectal cancers. APMIS. 119:562–564. 2011. View Article : Google Scholar : PubMed/NCBI

16 

Miyagaki H, Yamasaki M, Takahashi T, Kurokawa Y, Miyata H, Nakajima K, Takiguchi S, Fujiwara Y, Mori M and Doki Y: DOK2 as a marker of poor prognosis of patients with gastric adenocarcinoma after curative resection. Ann Surg Oncol. 19:1560–1567. 2012. View Article : Google Scholar

17 

Yamanashi Y, Higuch O and Beeson D: Dok-7/MuSK signaling and a congenital myasthenic syndrome. Acta Myol. 27:25–29. 2008.PubMed/NCBI

18 

Okada K, Inoue A, Okada M, Murata Y, Kakuta S, Jigami T, Kubo S, Shiraishi H, Eguchi K, Motomura M, et al: The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. Science. 312:1802–1805. 2006. View Article : Google Scholar : PubMed/NCBI

19 

Yang SM, Li SY, Yu HB, Li JR and Sun LL: Repression of DOK7 mediated by DNMT3A promotes the proliferation and invasion of KYSE410 and TE-12 ESCC cells. Biomed Pharmacother. 90:93–99. 2017. View Article : Google Scholar : PubMed/NCBI

20 

Hamuro J, Higuchi O, Okada K, Ueno M, Iemura S, Natsume T, Spearman H, Beeson D and Yamanashi Y: Mutations causing DOK7 congenital myasthenia ablate functional motifs in Dok-7. J Biol Chem. 283:5518–5524. 2008. View Article : Google Scholar : PubMed/NCBI

21 

Hallock PT, Xu CF, Park TJ, Neubert TA, Curran T and Burden SJ: Dok-7 regulates neuromuscular synapse formation by recruiting Crk and Crk-L. Genes Dev. 24:2451–2461. 2010. View Article : Google Scholar : PubMed/NCBI

22 

Mayer BJ, Ren R, Clark KL and Baltimore D: A putative modular domain present in diverse signaling proteins. Cell. 73:629–630. 1993. View Article : Google Scholar : PubMed/NCBI

23 

Pawson T: Protein modules and signalling networks. Nature. 373:573–580. 1995. View Article : Google Scholar : PubMed/NCBI

24 

Saraste M and Hyvönen M: Pleckstrin homology domains: A fact file. Curr Opin Struct Biol. 5:403–408. 1995. View Article : Google Scholar : PubMed/NCBI

25 

Chen G, Yu H, Satherley L, Zabkiewicz C, Resaul J, Zhao H, Mu H, Zhi X, He J, Ye L, et al: The downstream of tyrosine kinase 7 is reduced in lung cancer and is associated with poor survival of patients with lung cancer. Oncol Rep. 37:2695–2701. 2017. View Article : Google Scholar : PubMed/NCBI

26 

Zhao H, Yu H, Martin TA, Zhang Y, Chen G and Jiang WG: Effect of junctional adhesion molecule-2 expression on cell growth, invasion and migration in human colorectal cancer. Int J Oncol. 48:929–936. 2016. View Article : Google Scholar : PubMed/NCBI

27 

Berger AH, Chen M, Morotti A, Janas JA, Niki M, Bronson RT, Taylor BS, Ladanyi M, Van Aelst L, Politi K, et al: DOK2 inhibits EGFR-mutated lung adenocarcinoma. PLoS One. 8:e795262013. View Article : Google Scholar : PubMed/NCBI

28 

Bergamin E, Hallock PT, Burden SJ and Hubbard SR: The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization. Mol Cell. 39:100–109. 2010. View Article : Google Scholar : PubMed/NCBI

29 

Buyan A, Kalli AC and Sansom MS: Multiscale Simulations Suggest a Mechanism for the Association of the Dok 7 PH Domain with PIP-Containing Membranes. PLOS Comput Biol. 12:e10050282016. View Article : Google Scholar

30 

Chen QY and Costa M: PI3K/Akt/mTOR Signaling Pathway and the Biphasic Effect of Arsenic in Carcinogenesis. Mol Pharmacol. 94:784–792. 2018. View Article : Google Scholar : PubMed/NCBI

31 

Shi H, Pu J, Zhou XL, Ning YY and Bai C: Silencing long non-coding RNA ROR improves sensitivity of non-small-cell lung cancer to cisplatin resistance by inhibiting PI3K/Akt/mTOR signaling pathway. Tumour Biol. 39:10104283176975682017. View Article : Google Scholar : PubMed/NCBI

32 

Zhu J, Yao J, Huang R, Wang Y, Jia M and Huang Y: Ghrelin promotes human non-small cell lung cancer A549 cell proliferation through PI3K/Akt/mTOR/P70S6K and ERK signaling pathways. Biochem Biophys Res Commun. 498:616–620. 2018. View Article : Google Scholar : PubMed/NCBI

33 

Lv X, Li CY, Han P and Xu XY: MicroRNA-520a-3p inhibits cell growth and metastasis of non-small cell lung cancer through PI3K/AKT/mTOR signaling pathway. Eur Rev Med Pharmacol Sci. 22:2321–2327. 2018.PubMed/NCBI

34 

Cui S, Wang J, Wu Q, Qian J, Yang C and Bo P: Genistein inhibits the growth and regulates the migration and invasion abilities of melanoma cells via the FAK/paxillin and MAPK pathways. Oncotarget. 8:21674–21691. 2017.PubMed/NCBI

35 

Du T, Qu Y, Li J, Li H, Su L, Zhou Q, Yan M, Li C, Zhu Z and Liu B: Maternal embryonic leucine zipper kinase enhances gastric cancer progression via the FAK/Paxillin pathway. Mol Cancer. 13:1002014. View Article : Google Scholar : PubMed/NCBI

36 

Lu XS, Sun W, Ge CY, Zhang WZ and Fan YZ: Contribution of the PI3K/MMPs/Ln-5γ2 and EphA2/FAK/Paxillin signaling pathways to tumor growth and vasculogenic mimicry of gallbladder carcinomas. Int J Oncol. 42:2103–2115. 2013. View Article : Google Scholar : PubMed/NCBI

37 

Hu YL, Lu S, Szeto KW, Sun J, Wang Y, Lasheras JC and Chien S: FAK and paxillin dynamics at focal adhesions in the protrusions of migrating cells. Sci Rep. 4:60242014. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
APA
Zhao, H., Chen, G., Ye, L., Yu, H., Li, S., & Jiang, W.G. (2019). DOK7V1 influences the malignant phenotype of lung cancer cells through PI3K/AKT/mTOR and FAK/paxillin signaling pathways. International Journal of Oncology, 54, 381-389. https://doi.org/10.3892/ijo.2018.4624
MLA
Zhao, H., Chen, G., Ye, L., Yu, H., Li, S., Jiang, W. G."DOK7V1 influences the malignant phenotype of lung cancer cells through PI3K/AKT/mTOR and FAK/paxillin signaling pathways". International Journal of Oncology 54.1 (2019): 381-389.
Chicago
Zhao, H., Chen, G., Ye, L., Yu, H., Li, S., Jiang, W. G."DOK7V1 influences the malignant phenotype of lung cancer cells through PI3K/AKT/mTOR and FAK/paxillin signaling pathways". International Journal of Oncology 54, no. 1 (2019): 381-389. https://doi.org/10.3892/ijo.2018.4624