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Gene Review

Dok1  -  docking protein 1

Mus musculus

Synonyms: AW557123, Docking protein 1, Dok, Downstream of tyrosine kinase 1, p62(dok), ...
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Disease relevance of Dok1


High impact information on Dok1

  • FRS2 functions as a lipid-anchored docking protein that targets signaling molecules to the plasma membrane in response to FGF stimulation to link receptor activation with the MAPK and other signaling pathways essential for cell growth and differentiation [6].
  • Role of the rasGAP-associated docking protein p62(dok) in negative regulation of B cell receptor-mediated signaling [7].
  • Dok-1 and Dok-2 are adaptor proteins that negatively regulate Ras-Erk signaling downstream of protein tyrosine kinases (PTKs) [8].
  • Role of Dok-1 and Dok-2 in myeloid homeostasis and suppression of leukemia [2].
  • We have identified a family of proteins, Dok (downstream of tyrosine kinase), coexpressed in hematopoietic progenitor cells [3].

Chemical compound and disease context of Dok1


Biological context of Dok1


Anatomical context of Dok1

  • c-Abl phosphorylates Dok1 to promote filopodia during cell spreading [11].
  • Using an unbiased approach, we identified Dok1 as a specific c-Abl substrate in spreading fibroblasts [11].
  • Our data suggest a novel pathway by which c-Abl transduces signals to the actin cytoskeleton through phosphorylating Dok1 Y361 and recruiting Nck [11].
  • These data indicate that both SHIP and Dok1 functionally regulate the activation of Ras-Erk pathway by v-Abl and affect the mitogenic activity of v-Abl transformed bone marrow cells [14].
  • Transient expression of either Gq- or Gi-coupled receptors in COS-7 cells allowed GPCR agonist-induced EGFR transactivation, and lysophosphatidic acid (LPA)-generated signals involved the docking protein Gab1 [15].

Associations of Dok1 with chemical compounds

  • Src-induced tyrosine phosphorylation prevented the LMB-mediated nuclear accumulation of Dok1 [12].
  • Here we report the crystal structure of the Dok1 PTB domain alone and in complex with a phosphopeptide derived from RET receptor tyrosine kinase [16].
  • The N-terminal phosphotyrosine binding (PTB) domain of Dok1 can recognize and bind specifically to phosphotyrosine-containing motifs of receptors [16].
  • Because the SH2-containing inositol 5'-phosphatase (SHIP) and Downstream of tyrosine kinase 1 (Dok1) have been shown to interact with Abl, the effect of SHIP and Dok1 deficiency on v-Abl transformation was investigated [14].
  • Differential regulation of adapter proteins Dok2 and Dok1 in platelets, leading to an association of Dok2 with integrin alphabeta [17].

Physical interactions of Dok1

  • Addition of the K-Ras membrane-targeting motif to Dok-1 generated a constitutively membrane-bound Dok-1 protein whose tyrosine phosphorylation was independent of PI 3-kinase [18].
  • However, the Dok-1 mutant having YF substitutions at the rasGAP-binding sites (Tyr-295 and Tyr-361) also showed incapability of Ras and Erk inhibition [19].

Enzymatic interactions of Dok1


Regulatory relationships of Dok1

  • Lyn promoted phosphorylation of c-Kit and association of c-Kit and Dok-1 [18].
  • Here we show that stimulation of Mo7 hematopoietic cells with c-Kit ligand (KL) induces phosphatidylinositol (PI) 3-kinase-dependent tyrosine phosphorylation and membrane recruitment of Dok-1 [18].
  • Mutations of this domain or Tyr(146) that block homodimerization significantly reduce the ability of Dok to inhibit Src transformation [21].

Other interactions of Dok1

  • Complementation of SHIP(-/-) or Dok1(-/-) cells abrogates their hyperproliferation and intracellular Erk activation [14].
  • Furthermore, treatment of these cells with either a farnesyltransferase inhibitor or a MEK1/2 inhibitor abrogates the increased proliferation of SHIP(-/-) or Dok1(-/-) cells in a dose-dependent manner [14].
  • The RET phosphopeptide binds to Dok1 via a surface groove formed between strand beta5 and the C-terminal alpha-helix of the PTB domain [16].
  • Phosphatidylinositol 3-kinase and Src family kinases are required for phosphorylation and membrane recruitment of Dok-1 in c-Kit signaling [18].
  • However, the use of primary bone marrow mast cells from normal and Lyn-deficient mice demonstrated that Lyn is required for KL-dependent Dok-1 tyrosine phosphorylation [18].

Analytical, diagnostic and therapeutic context of Dok1


  1. Dok1 encoding p62(dok) maps to mouse chromosome 6 and human chromosome 2 in a region of translocation in chronic lymphocytic leukemia. Nelms, K., Snow, A.J., Noben-Trauth, K. Genomics (1998) [Pubmed]
  2. Role of Dok-1 and Dok-2 in myeloid homeostasis and suppression of leukemia. 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. J. Exp. Med. (2004) [Pubmed]
  3. Role of Dok-1 and Dok-2 in leukemia suppression. Niki, M., Di Cristofano, A., Zhao, M., Honda, H., Hirai, H., Van Aelst, L., Cordon-Cardo, C., Pandolfi, P.P. J. Exp. Med. (2004) [Pubmed]
  4. Inhibition of the motility and growth of B16F10 mouse melanoma cells by dominant negative mutants of Dok-1. Hosooka, T., Noguchi, T., Nagai, H., Horikawa, T., Matozaki, T., Ichihashi, M., Kasuga, M. Mol. Cell. Biol. (2001) [Pubmed]
  5. Association of CD2AP with dynamic actin on vesicles in podocytes. Welsch, T., Endlich, N., Gökce, G., Doroshenko, E., Simpson, J.C., Kriz, W., Shaw, A.S., Endlich, K. Am. J. Physiol. Renal Physiol. (2005) [Pubmed]
  6. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Kouhara, H., Hadari, Y.R., Spivak-Kroizman, T., Schilling, J., Bar-Sagi, D., Lax, I., Schlessinger, J. Cell (1997) [Pubmed]
  7. Role of the rasGAP-associated docking protein p62(dok) in negative regulation of B cell receptor-mediated signaling. Yamanashi, Y., Tamura, T., Kanamori, T., Yamane, H., Nariuchi, H., Yamamoto, T., Baltimore, D. Genes Dev. (2000) [Pubmed]
  8. Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling. Shinohara, H., Inoue, A., Toyama-Sorimachi, N., Nagai, Y., Yasuda, T., Suzuki, H., Horai, R., Iwakura, Y., Yamamoto, T., Karasuyama, H., Miyake, K., Yamanashi, Y. J. Exp. Med. (2005) [Pubmed]
  9. Calreticulin-integrin bidirectional signaling complex. Zhu, Q., Zelinka, P., White, T., Tanzer, M.L. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  10. Effect of herpes simplex virus type-1 UL41 gene on the stability of mRNA from the cellular genes: beta-actin, fibronectin, glucose transporter-1, and docking protein, and on virus intraperitoneal pathogenicity to newborn mice. Becker, Y., Tavor, E., Asher, Y., Berkowitz, C., Moyal, M. Virus Genes (1993) [Pubmed]
  11. c-Abl phosphorylates Dok1 to promote filopodia during cell spreading. Woodring, P.J., Meisenhelder, J., Johnson, S.A., Zhou, G.L., Field, J., Shah, K., Bladt, F., Pawson, T., Niki, M., Pandolfi, P.P., Wang, J.Y., Hunter, T. J. Cell Biol. (2004) [Pubmed]
  12. A nuclear export signal and phosphorylation regulate Dok1 subcellular localization and functions. Niu, Y., Roy, F., Saltel, F., Andrieu-Soler, C., Dong, W., Chantegrel, A.L., Accardi, R., Thépot, A., Foiselle, N., Tommasino, M., Jurdic, P., Sylla, B.S. Mol. Cell. Biol. (2006) [Pubmed]
  13. Role of Dok1 in cell signaling mediated by RET tyrosine kinase. Murakami, H., Yamamura, Y., Shimono, Y., Kawai, K., Kurokawa, K., Takahashi, M. J. Biol. Chem. (2002) [Pubmed]
  14. Dok1 and SHIP act as negative regulators of v-Abl-induced pre-B cell transformation, proliferation and Ras/Erk activation. Oki, S., Limnander, A., Yao, P.M., Niki, M., Pandolfi, P.P., Rothman, P.B. Cell Cycle (2005) [Pubmed]
  15. Signal characteristics of G protein-transactivated EGF receptor. Daub, H., Wallasch, C., Lankenau, A., Herrlich, A., Ullrich, A. EMBO J. (1997) [Pubmed]
  16. Structural basis for the specific recognition of RET by the Dok1 phosphotyrosine binding domain. Shi, N., Ye, S., Bartlam, M., Yang, M., Wu, J., Liu, Y., Sun, F., Han, X., Peng, X., Qiang, B., Yuan, J., Rao, Z. J. Biol. Chem. (2004) [Pubmed]
  17. Differential regulation of adapter proteins Dok2 and Dok1 in platelets, leading to an association of Dok2 with integrin alphabeta. Hughan, S.C., Watson, S.P. J. Thromb. Haemost. (2007) [Pubmed]
  18. Phosphatidylinositol 3-kinase and Src family kinases are required for phosphorylation and membrane recruitment of Dok-1 in c-Kit signaling. Liang, X., Wisniewski, D., Strife, A., Shivakrupa, n.u.l.l., Clarkson, B., Resh, M.D. J. Biol. Chem. (2002) [Pubmed]
  19. Dok-1 tyrosine residues at 336 and 340 are essential for the negative regulation of Ras-Erk signalling, but dispensable for rasGAP-binding. Shinohara, H., Yasuda, T., Yamanashi, Y. Genes Cells (2004) [Pubmed]
  20. The docking protein Cas links tyrosine phosphorylation signaling to elongation of cerebellar granule cell axons. Huang, J., Sakai, R., Furuichi, T. Mol. Biol. Cell (2006) [Pubmed]
  21. Domain-dependent function of the rasGAP-binding protein p62Dok in cell signaling. Songyang, Z., Yamanashi, Y., Liu, D., Baltimore, D. J. Biol. Chem. (2001) [Pubmed]
  22. Tyrosine phosphorylation of p62(Dok) induced by cell adhesion and insulin: possible role in cell migration. Noguchi, T., Matozaki, T., Inagaki, K., Tsuda, M., Fukunaga, K., Kitamura, Y., Kitamura, T., Shii, K., Yamanashi, Y., Kasuga, M. EMBO J. (1999) [Pubmed]
  23. Essential role of Gab1 for signaling by the c-Met receptor in vivo. Sachs, M., Brohmann, H., Zechner, D., Müller, T., Hülsken, J., Walther, I., Schaeper, U., Birchmeier, C., Birchmeier, W. J. Cell Biol. (2000) [Pubmed]
  24. Immunomodulation by Dok Din Daeng (Aeginetia indica Roxb.) extracts in female B6C3F1 mice: (I): stimulation of T cells. Auttachoat, W., Chitsomboon, B., Peachee, V.L., Guo, T.L., White, K.L. Int. Immunopharmacol. (2004) [Pubmed]
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