Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Genes & Dev. 14 (1): 11-16

Copyright © 2000 by Cold Spring Harbor Laboratory Press.

Vol. 14, No. 1, pp. 11-16, January 1, 2000

Role of the rasGAP-associated docking protein p62dok in negative regulation of B cell receptor-mediated signaling

Yuji Yamanashi,1,2 Toshiki Tamura,3 Toshihide Kanamori,1 Hidehiro Yamane,3 Hideo Nariuchi,3 Tadashi Yamamoto,1 and David Baltimore4

1 Departments of Oncology and 3 Allergology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo108-8639, Japan; 4 California Institute of Technology, Pasadena, California 91125 USA

Antigenic stimulation of the B-cell receptor (BCR) is a central event in the immune response. In contrast, antigen bound to IgG negatively regulates signals from the BCR by cross-linking it to the inhibitory receptor Fcgamma RIIB. Here we show that upon cross-linking of BCR or BCR with Fcgamma RIIB, the rasGAP-associated protein p62dok is prominently tyrosine phosphorylated in a Lyn-dependent manner. Inactivation of the dok gene by homologous recombination has shown that upon BCR cross-linking, p62dok suppresses MAP kinase and is indispensable for Fcgamma RIIB-mediated negative regulation of cell proliferation. We propose that p62dok, a downstream target of many PTKs, plays a negative role in various signaling situations.

[Key Words: Dok; Lyn; B cell receptor; Fcgamma RIIB; tyrosine kinase; MAP kinase]

2 Corresponding author.

GENES & DEVELOPMENT 14:11-16 © 2000 by Cold Spring Harbor Laboratory Press  ISSN 0890-9369/00 $5.00

Dok-2 Adaptor Protein Regulates the Shear-dependent Adhesive Function of Platelet Integrin {alpha}IIb{beta}3 in Mice.
S. C. Hughan, C. M. Spring, S. M. Schoenwaelder, S. Sturgeon, I. Alwis, Y. Yuan, J. D. McFadyen, E. Westein, D. Goddard, A. Ono, et al. (2014)
J. Biol. Chem. 289, 5051-5060
   Abstract »    Full Text »    PDF »
Localized Diacylglycerol-dependent Stimulation of Ras and Rap1 during Phagocytosis.
R. J. Botelho, R. E. Harrison, J. C. Stone, J. F. Hancock, M. R. Philips, J. Jongstra-Bilen, D. Mason, J. Plumb, M. R. Gold, and S. Grinstein (2009)
J. Biol. Chem. 284, 28522-28532
   Abstract »    Full Text »    PDF »
Essential Roles for Dok2 and RasGAP in CD200 Receptor-Mediated Regulation of Human Myeloid Cells.
R. Mihrshahi, A. N. Barclay, and M. H. Brown (2009)
J. Immunol. 183, 4879-4886
   Abstract »    Full Text »    PDF »
The Inhibitory Fc{gamma}IIb Receptor Dampens TLR4-Mediated Immune Responses and Is Selectively Up-regulated on Dendritic Cells from Rheumatoid Arthritis Patients with Quiescent Disease.
M. H. Wenink, K. C. M. Santegoets, M. F. Roelofs, R. Huijbens, H. J. P. M. Koenen, R. van Beek, I. Joosten, F. Meyer-Wentrup, L. Mathsson, J. Ronnelid, et al. (2009)
J. Immunol. 183, 4509-4520
   Abstract »    Full Text »    PDF »
p21 Ras/Impedes Mitogenic Signal Propagation Regulates Cytokine Production and Migration in CD4 T Cells.
J. Czyzyk, H.-C. Chen, K. Bottomly, and R. A. Flavell (2008)
J. Biol. Chem. 283, 23004-23015
   Abstract »    Full Text »    PDF »
Dok-1 is a Positive Regulator of IL-4 Signalling and IgE Response.
A. Inoue, T. Yasuda, T. Yamamoto, and Y. Yamanashi (2007)
J. Biochem. 142, 257-263
   Abstract »    Full Text »    PDF »
Dok-3 plays a nonredundant role in negative regulation of B-cell activation.
C.-H. Ng, S. Xu, and K.-P. Lam (2007)
Blood 110, 259-266
   Abstract »    Full Text »    PDF »
Dok-1 and Dok-2 are negative regulators of T cell receptor signaling.
T. Yasuda, K. Bundo, A. Hino, K. Honda, A. Inoue, M. Shirakata, M. Osawa, T. Tamura, H. Nariuchi, H. Oda, et al. (2007)
Int. Immunol. 19, 487-495
   Abstract »    Full Text »    PDF »
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.
S. Dong, B. Corre, E. Foulon, E. Dufour, A. Veillette, O. Acuto, and F. Michel (2006)
J. Exp. Med. 203, 2509-2518
   Abstract »    Full Text »    PDF »
Lyn kinase promotes erythroblast expansion and late-stage development.
V. G. Karur, C. A. Lowell, P. Besmer, V. Agosti, and D. M. Wojchowski (2006)
Blood 108, 1524-1532
   Abstract »    Full Text »    PDF »
Nonspecific Desensitization, Functional Memory, and the Characteristics of SHIP Phosphorylation following IgE-Mediated Stimulation of Human Basophils.
D. MacGlashan Jr. and N. Vilarino (2006)
J. Immunol. 177, 1040-1051
   Abstract »    Full Text »    PDF »
A Nuclear Export Signal and Phosphorylation Regulate Dok1 Subcellular Localization and Functions.
Y. Niu, F. Roy, F. Saltel, C. Andrieu-Soler, W. Dong, A.-L. Chantegrel, R. Accardi, A. Thepot, N. Foiselle, M. Tommasino, et al. (2006)
Mol. Cell. Biol. 26, 4288-4301
   Abstract »    Full Text »    PDF »
Dok-1 Independently Attenuates Ras/Mitogen-Activated Protein Kinase and Src/c-Myc Pathways To Inhibit Platelet-Derived Growth Factor-Induced Mitogenesis.
M. Zhao, J. A. Janas, M. Niki, P. P. Pandolfi, and L. Van Aelst (2006)
Mol. Cell. Biol. 26, 2479-2489
   Abstract »    Full Text »    PDF »
Downstream of Tyrosine Kinases-1 and Src Homology 2-Containing Inositol 5'-Phosphatase Are Required for Regulation of CD4+CD25+ T Cell Development.
M. Kashiwada, G. Cattoretti, L. McKeag, T. Rouse, B. M. Showalter, U. Al-Alem, M. Niki, P. P. Pandolfi, E. H. Field, and P. B. Rothman (2006)
J. Immunol. 176, 3958-3965
   Abstract »    Full Text »    PDF »
Drosophila Dok is required for embryonic dorsal closure.
R. Biswas, D. Stein, and E. R. Stanley (2006)
Development 133, 217-227
   Abstract »    Full Text »    PDF »
Phosphotyrosine Binding-Mediated Oligomerization of Downstream of Tyrosine Kinase (Dok)-1 and Dok-2 Is Involved in CD2-Induced Dok Phosphorylation.
I. Boulay, J.-G. Nemorin, and P. Duplay (2005)
J. Immunol. 175, 4483-4489
   Abstract »    Full Text »    PDF »
Requirement for CD100-CD72 interactions in fine-tuning of B-cell antigen receptor signaling and homeostatic maintenance of the B-cell compartment.
A. Kumanogoh, T. Shikina, C. Watanabe, N. Takegahara, K. Suzuki, M. Yamamoto, H. Takamatsu, D. V. R. Prasad, M. Mizui, T. Toyofuku, et al. (2005)
Int. Immunol. 17, 1277-1282
   Abstract »    Full Text »    PDF »
Dok-R Mediates Attenuation of Epidermal Growth Factor-Dependent Mitogen-Activated Protein Kinase and Akt Activation through Processive Recruitment of c-Src and Csk.
P. Van Slyke, M. L. Coll, Z. Master, H. Kim, J. Filmus, and D. J. Dumont (2005)
Mol. Cell. Biol. 25, 3831-3841
   Abstract »    Full Text »    PDF »
Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling.
H. Shinohara, A. Inoue, N. Toyama-Sorimachi, Y. Nagai, T. Yasuda, H. Suzuki, R. Horai, Y. Iwakura, T. Yamamoto, H. Karasuyama, et al. (2005)
J. Exp. Med. 201, 333-339
   Abstract »    Full Text »    PDF »
Stromal cell-derived factor-1{alpha}/CXCL12-induced chemotaxis of T cells involves activation of the RasGAP-associated docking protein p62Dok-1.
S. Okabe, S. Fukuda, Y.-J. Kim, M. Niki, L. M. Pelus, K. Ohyashiki, P. P. Pandolfi, and H. E. Broxmeyer (2005)
Blood 105, 474-480
   Abstract »    Full Text »    PDF »
Role of Dok-1 and Dok-2 in Myeloid Homeostasis and Suppression of Leukemia.
T. Yasuda, M. Shirakata, A. Iwama, A. Ishii, Y. Ebihara, M. Osawa, K. Honda, H. Shinohara, K. Sudo, K. Tsuji, et al. (2004)
J. Exp. Med. 200, 1681-1687
   Abstract »    Full Text »    PDF »
Role of Dok-1 and Dok-2 in Leukemia Suppression.
M. Niki, A. Di Cristofano, M. Zhao, H. Honda, H. Hirai, L. Van Aelst, C. Cordon-Cardo, and P. P. Pandolfi (2004)
J. Exp. Med. 200, 1689-1695
   Abstract »    Full Text »    PDF »
I{kappa}B kinase {beta} phosphorylates Dok1 serines in response to TNF, IL-1, or {gamma} radiation.
S. Lee, C. Andrieu, F. Saltel, O. Destaing, J. Auclair, V. Pouchkine, J. Michelon, B. Salaun, R. Kobayashi, P. Jurdic, et al. (2004)
PNAS 101, 17416-17421
   Abstract »    Full Text »    PDF »
Molecular Mechanisms of CD200 Inhibition of Mast Cell Activation.
S. Zhang, H. Cherwinski, J. D. Sedgwick, and J. H. Phillips (2004)
J. Immunol. 173, 6786-6793
   Abstract »    Full Text »    PDF »
Dok-6, a Novel p62 Dok Family Member, Promotes Ret-mediated Neurite Outgrowth.
R. J. Crowder, H. Enomoto, M. Yang, E. M. Johnson Jr., and J. Milbrandt (2004)
J. Biol. Chem. 279, 42072-42081
   Abstract »    Full Text »    PDF »
Tyrosine-phosphorylated SOCS3 Interacts with the Nck and Crk-L Adapter Proteins and Regulates Nck Activation.
J. C. Sitko, C. I. Guevara, and N. A. Cacalano (2004)
J. Biol. Chem. 279, 37662-37669
   Abstract »    Full Text »    PDF »
Co-aggregation of Fc{gamma}RII with Fc{epsilon}RI on Human Mast Cells Inhibits Antigen-induced Secretion and Involves SHIP-Grb2-Dok Complexes.
C. L. Kepley, S. Taghavi, G. Mackay, D. Zhu, P. A. Morel, K. Zhang, J. J. Ryan, L. S. Satin, M. Zhang, P. P. Pandolfi, et al. (2004)
J. Biol. Chem. 279, 35139-35149
   Abstract »    Full Text »    PDF »
c-Abl phosphorylates Dok1 to promote filopodia during cell spreading.
P. J. Woodring, J. Meisenhelder, S. A. Johnson, G.-L. Zhou, J. Field, K. Shah, F. Bladt, T. Pawson, M. Niki, P. P. Pandolfi, et al. (2004)
J. Cell Biol. 165, 493-503
   Abstract »    Full Text »    PDF »
Pleckstrin Homology and Phosphotyrosine-binding Domain-dependent Membrane Association and Tyrosine Phosphorylation of Dok-4, an Inhibitory Adapter Molecule Expressed in Epithelial Cells.
A. Bedirian, C. Baldwin, J.-i. Abe, T. Takano, and S. Lemay (2004)
J. Biol. Chem. 279, 19335-19349
   Abstract »    Full Text »    PDF »
Modification of Ligand-independent B Cell Receptor Tonic Signals Activates Receptor Editing in Immature B Lymphocytes.
Z. Keren, E. Diamant, O. Ostrovsky, E. Bengal, and D. Melamed (2004)
J. Biol. Chem. 279, 13418-13424
   Abstract »    Full Text »    PDF »
Requirement for Ras Guanine Nucleotide Releasing Protein 3 in Coupling Phospholipase C-{gamma}2 to Ras in B Cell Receptor Signaling.
M. Oh-hora, S. Johmura, A. Hashimoto, M. Hikida, and T. Kurosaki (2003)
J. Exp. Med. 198, 1841-1851
   Abstract »    Full Text »    PDF »
The inhibitory potential of Fc receptor homolog 4 on memory B cells.
G. R. A. Ehrhardt, R. S. Davis, J. T. Hsu, C.-M. Leu, A. Ehrhardt, and M. D. Cooper (2003)
PNAS 100, 13489-13494
   Abstract »    Full Text »    PDF »
Two New Substrates in Insulin Signaling, IRS5/DOK4 and IRS6/DOK5.
D. Cai, S. Dhe-Paganon, P. A. Melendez, J. Lee, and S. E. Shoelson (2003)
J. Biol. Chem. 278, 25323-25330
   Abstract »    Full Text »    PDF »
Modulation of Smad2-mediated Signaling by Extracellular Signal-regulated Kinase.
M. Funaba, C. M. Zimmerman, and L. S. Mathews (2002)
J. Biol. Chem. 277, 41361-41368
   Abstract »    Full Text »    PDF »
Dok-related protein negatively regulates T cell development via its RasGTPase-activating protein and Nck docking sites.
R. Gugasyan, C. Quilici, S. T.T. I, D. Grail, A. M. Verhagen, A. Roberts, T. Kitamura, A. R. Dunn, and P. Lock (2002)
J. Cell Biol. 158, 115-125
   Abstract »    Full Text »    PDF »
Downstream of Kinase, p62dok, Is a Mediator of Fc{gamma}RIIB Inhibition of Fc{epsilon}RI Signaling.
V. L. Ott, I. Tamir, M. Niki, P. P. Pandolfi, and J. C. Cambier (2002)
J. Immunol. 168, 4430-4439
   Abstract »    Full Text »    PDF »
Phosphatidylinositol 3-Kinase and Src Family Kinases Are Required for Phosphorylation and Membrane Recruitment of Dok-1 in c-Kit Signaling.
X. Liang, D. Wisniewski, A. Strife, Shivakrupa, B. Clarkson, and M. D. Resh (2002)
J. Biol. Chem. 277, 13732-13738
   Abstract »    Full Text »    PDF »
The rasGAP-binding protein, Dok-1, mediates activin signaling via serine/threonine kinase receptors.
N. Yamakawa, K. Tsuchida, and H. Sugino (2002)
EMBO J. 21, 1684-1694
   Abstract »    Full Text »    PDF »
T Cell Regulation of p62dok (Dok1) Association with Crk-L.
M. P. Martelli, J. Boomer, M. Bu, and B. E. Bierer (2001)
J. Biol. Chem. 276, 45654-45661
   Abstract »    Full Text »    PDF »
Insulin Receptor-mediated p62dok Tyrosine Phosphorylation at Residues 362 and 398 Plays Distinct Roles for Binding GTPase-activating Protein and Nck and Is Essential for Inhibiting Insulin-stimulated Activation of Ras and Akt.
M. J. Wick, L. Q. Dong, D. Hu, P. Langlais, and F. Liu (2001)
J. Biol. Chem. 276, 42843-42850
   Abstract »    Full Text »    PDF »
Downregulation of the Ras-Mitogen-Activated Protein Kinase Pathway by the EphB2 Receptor Tyrosine Kinase Is Required for Ephrin-Induced Neurite Retraction.
S. Elowe, S. J. Holland, S. Kulkarni, and T. Pawson (2001)
Mol. Cell. Biol. 21, 7429-7441
   Abstract »    Full Text »    PDF »
Multiple ErbB-2/Neu Phosphorylation Sites Mediate Transformation through Distinct Effector Proteins.
D. Dankort, N. Jeyabalan, N. Jones, D. J. Dumont, and W. J. Muller (2001)
J. Biol. Chem. 276, 38921-38928
   Abstract »    Full Text »    PDF »
Antiapoptotic Signaling Generated by Caspase-Induced Cleavage of RasGAP.
J.-Y. Yang and C. Widmann (2001)
Mol. Cell. Biol. 21, 5346-5358
   Abstract »    Full Text »    PDF »
Inhibition of the Motility and Growth of B16F10 Mouse Melanoma Cells by Dominant Negative Mutants of Dok-1.
T. Hosooka, T. Noguchi, H. Nagai, T. Horikawa, T. Matozaki, M. Ichihashi, and M. Kasuga (2001)
Mol. Cell. Biol. 21, 5437-5446
   Abstract »    Full Text »    PDF »
P62dok, a Negative Regulator of Ras and Mitogen-Activated Protein Kinase (Mapk) Activity, Opposes Leukemogenesis by P210bcr-abl.
A. Di Cristofano, M. Niki, M. Zhao, F. G. Karnell, B. Clarkson, W. S. Pear, L. Van Aelst, and P. P. Pandolfi (2001)
J. Exp. Med. 194, 275-284
   Abstract »    Full Text »    PDF »
Phosphoinositide 3-Kinase-Dependent Membrane Recruitment of P62dok Is Essential for Its Negative Effect on Mitogen-Activated Protein (Map) Kinase Activation.
M. Zhao, A. A.P. Schmitz, Y. Qin, A. Di Cristofano, P. P. Pandolfi, and L. Van Aelst (2001)
J. Exp. Med. 194, 265-274
   Abstract »    Full Text »    PDF »
p62dok Negatively Regulates CD2 Signaling in Jurkat Cells.
J.-G. Nemorin, P. Laporte, G. Berube, and P. Duplay (2001)
J. Immunol. 166, 4408-4415
   Abstract »    Full Text »    PDF »
Mutational Analysis Reveals Multiple Distinct Sites Within Fc{gamma} Receptor IIB That Function in Inhibitory Signaling.
D. C. Fong, A. Brauweiler, S. A. Minskoff, P. Bruhns, I. Tamir, I. Mellman, M. Daeron, and J. C. Cambier (2000)
J. Immunol. 165, 4453-4462
   Abstract »    Full Text »    PDF »
p56dok-2 as a cytokine-inducible inhibitor of cell proliferation and signal transduction.
S. Suzu, M. Tanaka-Douzono, K. Nomaguchi, M. Yamada, H. Hayasawa, F. Kimura, and K. Motoyoshi (2000)
EMBO J. 19, 5114-5122
   Abstract »    Full Text »    PDF »
The X-linked lymphoproliferative syndrome gene product SH2D1A associates with p62dok (Dok1) and activates NF-kappa B.
B. S. Sylla, K. Murphy, E. Cahir-McFarland, W. S. Lane, G. Mosialos, and E. Kieff (2000)
PNAS 97, 7470-7475
   Abstract »    Full Text »    PDF »
Structure, function, and biology of SHIP proteins.
L. R. Rohrschneider, J. F. Fuller, I. Wolf, Y. Liu, and D. M. Lucas (2000)
Genes & Dev. 14, 505-520
   Full Text »
Novel p62dok family members, dok-4 and dok-5, are substrates of the c-Ret receptor tyrosine kinase and mediate neuronal differentiation.
J. Grimm, M. Sachs, S. Britsch, S. Di Cesare, T. Schwarz-Romond, K. Alitalo, and W. Birchmeier (2001)
J. Cell Biol. 154, 345-354
   Abstract »    Full Text »    PDF »
Domain-dependent Function of the rasGAP-binding Protein p62Dok in Cell Signaling.
Z. Songyang, Y. Yamanashi, D. Liu, and D. Baltimore (2001)
J. Biol. Chem. 276, 2459-2465
   Abstract »    Full Text »    PDF »
The X-linked lymphoproliferative syndrome gene product SH2D1A associates with p62dok (Dok1) and activates NF-kappa B.
B. S. Sylla, K. Murphy, E. Cahir-McFarland, W. S. Lane, G. Mosialos, and E. Kieff (2000)
PNAS 97, 7470-7475
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882