Cancer is a complex, multifactorial disease that modern medicine ultimately aims to overcome. Downstream of tyrosine kinase 2 (DOK2) is a well-known tumor suppressor gene, and a member of the downstream protein DOK family of tyrosine kinases. Through a search of original literature indexed in PubMed and other databases, the present review aims to extricate the mechanisms by which DOK2 acts on cancer, thereby identifying more reliable and effective therapeutic targets to promote enhanced methods of cancer prevention and treatment. The review focuses on the role of DOK2 in multiple tumor types in the lungs, intestines, liver, and breast. Additionally, we discuss the potential mechanisms of action of DOK2 and the downstream consequences via the Ras/MPAK/ERK or PI3K/AKT/mTOR signaling pathways.

Department of Pharmacology School of Basic Medicine Health Science Center Yangtze University Jingzhou Hubei China or Department of Pathophysiology School of Basic Medicine Health Science Center Yangtze University Jingzhou Hubei China or Department of Oncology 1st Affiliated Hospital of Yangtze University Jingzhou Hubei

Zobrazit více v PubMed

ABRAMSON J, PECHT I. Regulation of the mast cell response to the type 1 Fc epsilon receptor. Immunol Rev. 2007;217:231–254. doi: 10.1111/j.1600-065X.2007.00518.x. PubMed DOI

ÁLVAREZ De CELIS H, GÓMEZ CP, DESCOTEAUX A, DUPLAY P. Dok proteins are recruited to the phagosome and degraded in a GP63-dependent manner during Leishmania major infection. Microbes Infect. 2015;17:285–294. doi: 10.1016/j.micinf.2014.12.011. PubMed DOI

AMREIN L, HERNANDEZ TA, FERRARIO C, JOHNSTONJ, GIBSON SB, PANASCI L, ALOYZ R. Dasatinib sensitizes primary chronic lymphocytic leukaemia lymphocytes to chlorambucil and fludarabine in vitro. Br J Haematol. 2008;143:698–706. doi: 10.1111/j.1365-2141.2008.07418.x. PubMed DOI

ASATI V, MAHAPATRA DK, BHARTI SK. PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives. Eur J Med Chem. 2016;109:314–341. doi: 10.1016/j.ejmech.2016.01.012. PubMed DOI

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. 2010;42:216–223. doi: 10.1038/ng.527. PubMed DOI PMC

BERGER AH, CHEN M, MOROTTI A, JANAS JA, NIKI M, BRONSON RT, TAYLOR BS, LADANYI M, AELST LV, POLITI K, VARMUS HE, PANDOLFI PP. DOK2 inhibits EGFR-mutated lung adenocarcinoma. PLoS One. 2013;8:e79526. doi: 10.1371/journal.pone.0079526. PubMed DOI PMC

BIDKHORI G, NARIMANI Z, HOSSEINI ASHTIANI S, MOEINI A, NOWZARI-DALINI A, MASOUDI-NEJAD A. Reconstruction of an integrated genome-scale co-expression network reveals key modules involved in lung adenocarcinoma. PLoS One. 2013;8:e67552. doi: 10.1371/journal.pone.0067552. PubMed DOI PMC

BOULAY I, NÉMORIN JG, DUPLAY P. Phosphotyrosine binding-mediated oligomerization of downstream of tyrosine kinase (Dok)-1 and Dok-2 is involved in CD2-induced Dok phosphorylation. J Immunol. 2005;175:4483–4489. doi: 10.4049/jimmunol.175.7.4483. PubMed DOI

CELIS-GUTIERREZ J, BOYRON M, WALZER T, PANDOLFI PP, JONJIĆ S, OLIVE D, DALOD M, VIVIER E, NUNÈS JA. Dok1 and Dok2 proteins regulate natural killer cell development and function. EMBO J. 2014;133:1928–1940. doi: 10.15252/embj.201387404. PubMed DOI PMC

CHANG H, LEE YG, KO YH, CHO JH, CHOI JK, PARK KU, KANG EJ, LEE KW, LIM SM, KIM JS, ET AL. Prognostic value of CD200R1 mRNA expression in head and neck squamous cell carcinoma. Cancers. 2020;12:1777. doi: 10.3390/cancers12071777. PubMed DOI PMC

CHEN M, ZHANG J, BERGER AH, DIOLOMBI MS, NG C, FUNG J, BRONSON RT, CASTILLO-MARTIN M, THIN TH, CORDON-CARDO C, PLEVIN R, PANDOLFI PP. Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis. J Clin Invest. 2019;129:215–222. doi: 10.1172/JCI99699. PubMed DOI PMC

CHANG J, TIAN J, ZHU Y, ZHONG R, ZHAI K, LI J, KE J, HAN Q, LOU J, CHEN W, ET AL. Exome-wide analysis identifies three low-frequency missense variants associated with pancreatic cancer risk in Chinese populations. Nat Commun. 2018;9:3688. doi: 10.1038/s41467-018-06136-x. PubMed DOI PMC

COPPIN E, GELSI-BOYER V, MORELLI X, CERVERA N, MURATI A, PANDOLFI PP, BIRNBAUM D, NUNÈS JA. Mutational analysis of the DOK2 haploinsufficient tumor suppressor gene in chronic myelomonocytic leukemia (CMML) Leukemia. 2015;29:500–502. doi: 10.1038/leu.2014.288. PubMed DOI

COPPIN E, De GRANDIS M, PANDOLFI PP, ARCANGELI ML, AURRAND-LIONS M, NUNÈS JA. Dok1 and Dok2 proteins regulate cell cycle in hematopoietic stem and progenitor cells. J Immunol. 2016;196:4110–4121. doi: 10.4049/jimmunol.1501037. PubMed DOI

DESHPANDE RP, BABU PP. pDok2, caspase 3 dependent glioma cell growth arrest by nitidine chloride. Pharmacol Rep. 2018;70:48–54. doi: 10.1016/j.pharep.2017.07.013. PubMed DOI

DESHPANDE RP, CHANDRA SEKHAR Y, PANIGRAHI M, BABU PP. Region-specific Dok2 overexpression associates with poor prognosis in human astrocytoma. Mol Neurobiol. 2018;55:402–408. doi: 10.1007/s12035-016-0324-2. PubMed DOI

Di CRISTOFANO A, CARPINO N, DUNANT N, FRIEDLAND G, KOBAYASHI R, STRIFE A, WISNIEWSKI D, CLARKSON B, PANDOLFI PP, RESH MD. Molecular cloning and characterization of p56dok-2 defines a new family of RasGAP-binding proteins. J Biol Chem. 1998;273:4827–4830. doi: 10.1074/jbc.273.9.4827. PubMed DOI

DOWNER EJ, JOHNSTON DG, LYNCH MA. Differential role of Dok1 and Dok2 in TLR2-induced inflammatory signaling in glia. Mol Cell Neurosci. 2013;56:148–158. doi: 10.1016/j.mcn.2013.04.007. PubMed DOI

DONG S, CORRE B, FOULON E, DUFOUR E, VEILLETTE A, ACUTO O, MICHEL F. T cell receptor for antigen induces linker for activation of T cell-dependent activation of a negative signaling complex involving Dok-2, SHIP-1, and Grb-2. J Exp Med. 2006;203:2509–2518. doi: 10.1084/jem.20060650. PubMed DOI PMC

FANG F, CARDENAS H, HUANG H, JIANG G, PERKINS SM, ZHANG C, KEER HN, LIU Y, NEPHEW KP, MATEI D. Genomic and epigenomic signatures in ovarian cancer associated with resensitization to platinum drugs. Cancer Res. 2018;78:631–644. doi: 10.1158/0008-5472.CAN-17-1492. PubMed DOI PMC

GHANEM T, BRACKEN J, KASEM A, JIANG WG, MOKBEL K. mRNA expression of DOK1-6 in human breast cancer. World J Clin Oncol. 2014;5:156–163. doi: 10.5306/wjco.v5.i2.156. PubMed DOI PMC

GUGASYAN R, QUILICI C, I ST, GRAIL D, VERHAGEN AM, ROBERTS A, KITAMURA T, DUNN AR, LOCK P. Dok-related protein negatively regulates T cell development via its RasGTPase-activating protein and Nck docking sites. J Cell Biol. 2002;158:115–125. doi: 10.1083/jcb.200112066. PubMed DOI PMC

GUITTARD G, GÉRARD A, DUPUIS-CORONAS S, TRONCHÈRE H, MORTIER E, FAVRE C, OLIVE D, ZIMMERMANN P, PAYRASTRE B, NUNÈS JA. Cutting edge: Dok-1 and Dok-2 adaptor molecules are regulated by phosphatidylinositol 5-phosphate production in T cells. J Immunol. 2009;182:3974–3978. doi: 10.4049/jimmunol.0804172. PubMed DOI

GRIMM J, SACHS M, BRITSCH S, Di CESARE S, SCHWARZ-ROMOND T, ALITALO K, 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 Biology. 2001;154:345–354. doi: 10.1083/jcb.200102032. PubMed DOI PMC

GÉRARD A, FAVRE C, GARÇON F, NÉMORIN JG, DUPLAY P, PASTOR S, COLLETTE Y, OLIVE D, NUNÈS JA. Functional interaction of RasGAP-binding proteins Dok-1 and Dok-2 with the Tec protein tyrosine kinase. Oncogene. 2004;23:1594–1598. doi: 10.1038/sj.onc.1207283. PubMed DOI

HERBET A, COSTA N, LEVENTOUX N, MABONDZO A, COURAUD JY, BORRULL A, HUGNOT JP, BOQUET D. Antibodies targeting human endothelin-1 receptors reveal different conformational states in cancer cells. Physiol Res. 2018;67(Suppl 1):S257–S264. doi: 10.33549/physiolres.933848. PubMed DOI

HUGHAN SC, WATSON SP. Differential regulation of adapter proteins Dok2 and Dok1 in platelets, leading to an association of Dok2 with integrin alphaIIbbeta3. J Thromb Haemost. 2007;5:387–394. doi: 10.1111/j.1538-7836.2007.02307.x. PubMed DOI

HE PF, XU ZJ, ZHOU JD, LI XX, ZHANG W, WU DH, ZHANG ZH, LIAN XY, YAO XY, DENG ZQ, LIN J, QIAN J. Methylation-associated DOK1 and DOK2 down-regulation: Potential biomarkers for predicting adverse prognosis in acute myeloid leukemia. J Cell Physiol. 2018;233:6604–6614. doi: 10.1002/jcp.26271. PubMed DOI

HUANG J, PENG X, ZHANG K, LI C, SU B, ZHANG Y, YU W. Co-expression and significance of Dok2 and Ras p21 protein activator 1 in breast cancer. Oncol Lett. 2017;14:5386–5392. doi: 10.3892/ol.2017.6844. PubMed DOI PMC

JAMBOR T, KOVACIKOVA E, GREIFOVA H, KOVACIK A, LIBOVA L, LUKAC N. Assessment of the effective impact of bisphenols on mitochondrial activity and steroidogenesis in a dose-dependency in mice TM3 Leydig cells. Physiol Res. 2019;68:689–693. doi: 10.33549/physiolres.934200. PubMed DOI

JONES N, CHEN SH, STURK C, MASTER Z, TRAN J, KERBEL RS, DUMONT DJ. A unique autophosphorylation site on Tie2/Tek mediates Dok-R phosphotyrosine binding domain binding and function. Mol Cell Biol. 2003;23:2658–2668. doi: 10.1128/MCB.23.8.2658-2668.2003. PubMed DOI PMC

JONES N, 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. 1999;9:1057–1060. doi: 10.1016/S0960-9822(99)80458-8. PubMed DOI

KAJIKAWA S, TAGUCHI Y, HAYATA T, EZURA Y, UETA R, ARIMURA S, INOUE JI, NODA M, YAMANASHI Y. Dok-3 and Dok-1/-2 adaptors play distinctive roles in cell fusion and proliferation during osteoclastogenesis and cooperatively protect mice from osteopenia. Biochem Biophys Res Commun. 2018;498:967–974. doi: 10.1016/j.bbrc.2018.03.090. PubMed DOI

KUŽMA M, KILLINGER Z, JACKULIAK P, VAŇUGA P, HANS D, BINKLEY N, PAYER J. Pathophysiology of growth hormone secretion disorders and their impact on bone microstructure as measured by trabecular bone score. Physiol Res. 2019;68(Suppl 2):S121–S129. doi: 10.33549/physiolres.934303. PubMed DOI

LAROCHE-LEFEBVRE C, YOUSEFI M, DAUDELIN JF, CHARPENTIER T, TARRAB E, KLINCK R, LAMARRE A, LABRECQUE N, STÄGER S, DUPLAY P. Dok-1 and Dok-2 regulate the formation of memory CD8+ T cells. J Immunol. 2016;197:3618–3627. doi: 10.4049/jimmunol.1600385. PubMed DOI

LYONS A, DOWNER EJ, COSTELLO DA, MURPHY N, LYNCH MA. Dok2 mediates the CD200Fc attenuation of Aβ-induced changes in glia. J Neuroinflammation. 2012;9:107. doi: 10.1186/1742-2094-9-107. PubMed DOI PMC

LAHMIDI S, STRUNK U, SMILEY JR, PEARSON A, DUPLAY P. Herpes simplex virus 1 infection of T cells causes VP11/12-dependent phosphorylation and degradation of the cellular protein Dok-2. Virology. 2017;511:66–73. doi: 10.1016/j.virol.2017.08.018. PubMed DOI

LAHMIDI S, YOUSEFI M, DRIDI S, DUPLAY P, PEARSON A. Dok-1 and Dok-2 are required to maintain herpes simplex virus 1-specific CD8(+) T cells in a murine model of ocular infection. J Virol. 2017;91:e02297–16. doi: 10.1128/JVI.02297-16. PubMed DOI PMC

LAMKIN TJ, CHIN V, YEN A. All-trans retinoic acid induces p62DOK1 and p56DOK2 expression which enhances induced differentiation and G0 arrest of HL-60 leukemia cells. Am J Hematol. 2006;81:603–615. doi: 10.1002/ajh.20667. PubMed DOI

LIANG X, HAJIVANDI M, VEACH D, WISNIEWSKI D, CLARKSON B, RESH MD, POPE RM. Quantification of change in phosphorylation of BCR-ABL kinase and its substrates in response to Imatinib treatment in human chronic myelogenous leukemia cells. Proteomics. 2006;6:4554–4564. doi: 10.1002/pmic.200600109. PubMed DOI

LUM E, VIGLIOTTI M, BANERJEE N, CUTTER N, WRZESZCZYNSKI KO, KHAN S, KAMALAKARAN S, LEVINE DA, DIMITROVA N, LUCITO R. Loss of DOK2 induces carboplatin resistance in ovarian cancer via suppression of apoptosis. Gynecol Oncol. 2013;130:369–376. doi: 10.1016/j.ygyno.2013.05.002. PubMed DOI

MASHIMA R, ARIMURA S, KAJIKAWA S, ODA H, NAKAE S, YAMANASHI Y. Dok adaptors play anti-inflammatory roles in pulmonary homeostasis. Genes Cells. 2013;18:56–65. doi: 10.1111/gtc.12016. PubMed DOI

MASHIMA R, HISHIDA Y, TEZUKA T, YAMANASHI Y. The roles of Dok family adapters in immunoreceptor signaling. Immunol Rev. 2009;232:273–285. doi: 10.1111/j.1600-065X.2009.00844.x. PubMed DOI

MASHIMA R, HONDA K, YANG Y, MORITA Y, INOUE A, ARIMURA S, NISHINA H, EMA H, NAKAUCHI H, SEED B, ODA H, YAMANASHI Y. Mice lacking Dok-1, Dok-2, and Dok-3 succumb to aggressive histiocytic sarcoma. Lab Invest. 2010;90:1357–1364. doi: 10.1038/labinvest.2010.121. PubMed DOI

MASTER Z, JONES N, TRAN J, JONES J, KERBEL RS, DUMONT DJ. Dok-R plays a pivotal role in angiopoietin-1-dependent cell migration through recruitment and activation of Pak. EMBO J. 2001;20:5919–5928. doi: 10.1093/emboj/20.21.5919. PubMed DOI PMC

MIHRSHAHI R, BARCLAY AN, BROWN MH. Essential roles for Dok2 and RasGAP in CD200 receptor-mediated regulation of human myeloid cells. J Immunol. 2009;183:4879–4886. doi: 10.4049/jimmunol.0901531. PubMed DOI PMC

MIHRSHAHI R, BROWN MH. Downstream of tyrosine kinase 1 and 2 play opposing roles in CD200 receptor signaling. J Immunol. 2010;185:7216–7222. doi: 10.4049/jimmunol.1002858. PubMed DOI PMC

MIYAGAKI H, YAMASAKI M, TAKAHASHI T, KUROKAWA Y, MIYATA H, NAKAJIMA K, TAKIGUCHI S, FUJIWARA Y, MORI M, DOKI Y. DOK2 as a marker of poor prognosis of patients with gastric adenocarcinoma after curative resection. Ann Surg Oncol. 2012;19:1560–1567. doi: 10.1245/s10434-011-2157-6. PubMed DOI

MIYATA-TAKATA T, CHUANG SS, TAKATA K, TOJI T, MAEDA Y, SATO Y, YOSHINO T. Expression of T-cell receptor signalling pathway components in extranodal NK/T-cell lymphoma. Histopathology. 2018;73:1030–1038. doi: 10.1111/his.13728. PubMed DOI

NÉMORIN JG, DUPLAY P. Evidence that Llck-mediated phosphorylation of p56dok and p62dok may play a role in CD2 signaling. J Biol Chem. 2000;275:14590–14597. doi: 10.1074/jbc.275.19.14590. PubMed DOI

NIKI M, Di CRISTOFANO A, ZHAO M, HONDA H, HIRAI H, AELST LV, CORDON-CARDO C, PANDOLFI PP. Role of Dok-1 and Dok-2 in leukemia suppression. J Exp Med. 2004;200:1689–1695. doi: 10.1084/jem.20041306. PubMed DOI PMC

OHSUGI T, WAKAMIYA M, MORIKAWA S, FUJITA M. Expression of DOK1, 2, and 3 genes in HTLV-1-infected T cells. Acta Virol. 2016;60:211–213. doi: 10.4149/av_2016_02_211. PubMed DOI

OHSUGI T. Effects of expressing human T-cell leukemia virus type 1 (HTLV-I) oncoprotein Tax on DOK1, DOK2 and DOK3 gene expression in mice. J Vet Med Sci. 2017;79:935–938. doi: 10.1292/jvms.17-0034. PubMed DOI PMC

RIJKERS ESK, De RUITER T, BUITENHUIS M, VENINGA H, HOEK RM, MEYAARD L. Ligation of CD200R by CD200 is not required for normal murine myelopoiesis. Eur J Haematol. 2007;79:410–416. doi: 10.1111/j.1600-0609.2007.00920.x. PubMed DOI

SMITH MJ, HARDY WR, MURPHY JM, JONES N, PAWSON T. Screening for PTB domain binding partners and ligand specificity using proteome-derived NPXY peptide arrays. Mol Cell Biol. 2006;26:8461–8474. doi: 10.1128/MCB.01491-06. PubMed DOI PMC

SOLAREK W, KOPER M, LEWICKI S, SZCZYLIK C, CZARNECKA AM. Insulin and insulin-like growth factors act as renal cell cancer intratumoral regulators. J Cell Commun Signal. 2019;13:381–394. doi: 10.1007/s12079-019-00512-y. PubMed DOI PMC

SUZU S, TANAKA-DOUZONO M, NOMAGUCHI K, YAMADA M, HAYASAWA H, KIMURA F, MOTOYOSHI K. p56(dok-2) as a cytokine-inducible inhibitor of cell proliferation and signal transduction. EMBO J. 2000;19:5114–5122. doi: 10.1093/emboj/19.19.5114. PubMed DOI PMC

TANAKA Y, KULKEAW K, INOUE T, TAN KS, NAKANISHI Y, SHIRASAWA S, SUGIYAMA D. Dok2 likely down-regulates Klf1 in mouse erythroleukemia cells. Anticancer Res. 2014;34:4561–4567. PubMed

UETA R, TEZUKA T, IZAWA Y, MIYOSHI S, NAGATOISHI S, TSUMOTO K, YAMANASHI Y. The carboxyl-terminal region of Dok-7 plays a key, but not essential, role in activation of muscle-specific receptor kinase MuSK and neuromuscular synapse formation. J Biochem. 2017;161:269–277. doi: 10.1093/jb/mvw073. PubMed DOI

Van SLYKE P, COLL ML, MASTER Z, KIM H, FILMUS J, DUMONT DJ. Dok-R mediates attenuation of epidermal growth factor-dependent mitogen-activated protein kinase and Akt activation through processive recruitment of c-Src and Csk. Mol Cell Biol. 2005;25:3831–3841. doi: 10.1128/MCB.25.9.3831-3841.2005. PubMed DOI PMC

VÉLEZ P, OCARANZA-SÁNCHEZ R, LÓPEZ-OTERO D, GRIGORIAN-SHAMAGIAN L, ROSA I, GUITIÁN E, GARCÍA-ACUÑA JM, GONZÁLEZ-JUANATEY JR, GARCÍA A. Alteration of platelet GPVI signaling in ST-elevation myocardial infarction patients demonstrated by a combination of proteomic, biochemical, and functional approaches. Sci Rep. 2016;6:39603. doi: 10.1038/srep39603. PubMed DOI PMC

WATERMAN PM, MARSCHNER S, BRANDL E, CAMBIER JC. The inositol 5-phosphatase SHIP-1 and adaptors Dok-1 and 2 play central roles in CD4-mediated inhibitory signaling. Immunol Lett. 2012;143:122–130. doi: 10.1016/j.imlet.2012.02.009. PubMed DOI PMC

WEN X, ZHOU M, GUO Y, ZHU Y, LI H, ZHANG L, YU L, WANG X, PENG X. Expression and significance of DOK2 in colorectal cancer. Oncol Lett. 2015;9:241–244. doi: 10.3892/ol.2014.2672. PubMed DOI PMC

YASUDA T, SHIRAKATA M, IWAMA A, ISHII A, EBIHARA Y, OSAWA M, HONDA K, SHINOHARA H, SUDO K, TSUJI K, NAKAUCHI H, IWAKURA Y, HIRAI H, ODA H, YAMAMOTO T, YAMANASHI Y. Role of Dok-1 and Dok-2 in myeloid homeostasis and suppression of leukemia. J Exp Med. 2004;200:1681–1687. doi: 10.1084/jem.20041247. PubMed DOI PMC

YASUDA T, BUNDO K, HINO A, HONDA K, INOUE A, SHIRAKATA M, OSAWA M, TAMURA T, NARIUCHI H, ODA H, YAMAMOTO T, YAMANASHI Y. Dok-1 and Dok-2 are negative regulators of T cell receptor signaling. Int Immunol. 2007;19:487–495. doi: 10.1093/intimm/dxm015. PubMed DOI

ZHANG S, CHERWINSKI H, SEDGWICK JD, PHILLIPS JH. Molecular mechanisms of CD200 inhibition of mast cell activation. J Immunol. 2004;173:6786–6793. doi: 10.4049/jimmunol.173.11.6786. PubMed DOI

ZHANG S, PHILLIPS JH. Identification of tyrosine residues crucial for CD200R-mediated inhibition of mast cell activation. J Leukoc Biol. 2006;79:363–368. doi: 10.1189/jlb.0705398. PubMed DOI

ZHANG XW, WANG L, DING H. Long noncoding RNA AK089579 inhibits epithelial-to-mesenchymal transition of peritoneal mesothelial cells by competitively binding to microRNA-296-3p via DOK2 in peritoneal fibrosis. FASEB J. 2019;33:5112–5125. doi: 10.1096/fj.201801111RR. PubMed DOI

ZHANG Y, LI Y, WANG Q, SU B, XU H, SUN Y, SUN P, LI R, PENG X, CAI J. Role of RASA1 in cancer: A review and update (Review) Oncol Rep. 2020;44:2386–2396. doi: 10.3892/or.2020.7807. PubMed DOI PMC