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.

Subscribe

Logo for

J. Exp. Med. 194 (3): 265-274

Copyright © 2001 by the Rockefeller University Press.


Original Article

Phosphoinositide 3-Kinase–Dependent Membrane Recruitment of P62dok Is Essential for Its Negative Effect on Mitogen-Activated Protein (Map) Kinase Activation

Mingming Zhaoa,b, Arndt A.P. Schmitza, Yi Qina, Antonio Di Cristofanoc, Pier Paolo Pandolfic, , and Linda Van Aelsta,b

a Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
b Molecular and Cell Biology Graduate Program, State University of New York at Stony Brook, Stony Brook, New York 11733
c Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
Cold Spring Harbor Laboratory, 1 Bungtown Rd., Cold Spring Harbor, NY 11724.516-367-8815516-367-6829

vanaelst{at}cshl.org

Abstract: A major pathway by which growth factors, such as platelet-derived growth factor (PDGF), regulate cell proliferation is via the receptor tyrosine kinase/Ras/mitogen-activated protein kinase (MAPK) signaling cascade. The output of this pathway is subjected to tight regulation of both positive and negative regulators. One such regulator is p62dok, the prototype of a newly identified family of adaptor proteins. We recently provided evidence, through the use of p62dok-deficient cells, that p62dok acts as a negative regulator of growth factor–induced cell proliferation and the Ras/MAPK pathway. We show here that reintroduction of p62dok into p62dok/– cells can suppress the increased cell proliferation and prolonged MAPK activity seen in these cells, and that plasma membrane recruitment of p62dok is essential for its function. We also show that the PDGF-triggered plasma membrane translocation of p62dok requires activation of phosphoinositide 3-kinase (PI3-kinase) and binding of its pleckstrin homology (PH) domain to 3'-phosphorylated phosphoinositides. Furthermore, we demonstrate that p62dok can exert its negative effect on the PDGFR/MAPK pathway independently of its ability to associate with RasGAP and Nck. We conclude that p62dok functions as a negative regulator of the PDGFR/Ras/MAPK signaling pathway through a mechanism involving PI3-kinase–dependent recruitment of p62dok to the plasma membrane.

Key Words: growth factors • cell proliferation • membrane lipids • signal transduction • protein-serine-threonine kinase


A. Di Cristofano's present address is Human Genetics Program, Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111.

Abbreviations used in this paper: aa, amino acid(s); MAPK, mitogen-activated protein kinase; MEF, mouse embryo fibroblast; MLV, multilamellar vesicle; PC, phosphatidylcholine; PDGFR, platelet-derived growth factor receptor; PH, pleckstrin homology; PS, phosphatidylserine; PTB, phosphotyrosine binding; RT, room temperature; RTK, receptor tyrosine kinase; SHIP1, Src homology 2 domain–containing inositol 5-phosphatase; WT, wild-type.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation.
J. A. Janas and L. Van Aelst (2011)
Mol. Cell. Biol. 31, 2552-2565
   Abstract »    Full Text »    PDF »
Cutting Edge: Dok-1 and Dok-2 Adaptor Molecules Are Regulated by Phosphatidylinositol 5-Phosphate Production in T Cells.
G. Guittard, A. Gerard, S. Dupuis-Coronas, H. Tronchere, E. Mortier, C. Favre, D. Olive, P. Zimmermann, B. Payrastre, and J. A. Nunes (2009)
J. Immunol. 182, 3974-3978
   Abstract »    Full Text »    PDF »
Advances in Targeting IKK and IKK-Related Kinases for Cancer Therapy.
D.-F. Lee and M.-C. Hung (2008)
Clin. Cancer Res. 14, 5656-5662
   Abstract »    Full Text »    PDF »
Investigation of Protein-tyrosine Phosphatase 1B Function by Quantitative Proteomics.
P. Mertins, H. C. Eberl, J. Renkawitz, J. V. Olsen, M. L. Tremblay, M. Mann, A. Ullrich, and H. Daub (2008)
Mol. Cell. Proteomics 7, 1763-1777
   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 »
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 »
Mechanism of Cyclosporine-induced Overgrowth in Gingiva.
H.-J. Chae, M.-S. Ha, D.-H. Yun, H.-O. Pae, H.-T. Chung, S.-W. Chae, Y.-K. Jung, and H.-R. Kim (2006)
Journal of Dental Research 85, 515-519
   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 »
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 »
Divergent Roles of c-Src in Controlling Platelet-derived Growth Factor-dependent Signaling in Fibroblasts.
K. Shah and F. Vincent (2005)
Mol. Biol. Cell 16, 5418-5432
   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 »
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 »
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 »
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 »
The role of protein tyrosine phosphatase 1B in Ras signaling.
N. Dube, A. Cheng, and M. L. Tremblay (2004)
PNAS 101, 1834-1839
   Abstract »    Full Text »    PDF »
A Unique Autophosphorylation Site on Tie2/Tek Mediates Dok-R Phosphotyrosine Binding Domain Binding and Function.
N. Jones, S. H. Chen, C. Sturk, Z. Master, J. Tran, R. S. Kerbel, and D. J. Dumont (2003)
Mol. Cell. Biol. 23, 2658-2668
   Abstract »    Full Text »    PDF »
Cytokine Signaling and Hematopoietic Homeostasis Are Disrupted in Lnk-deficient Mice.
L. Velazquez, A. M. Cheng, H. E. Fleming, C. Furlonger, S. Vesely, A. Bernstein, C. J. Paige, and T. Pawson (2002)
J. Exp. Med. 195, 1599-1611
   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 »
Visualization of Negative Signaling in B Cells by Quantitative Confocal Microscopy.
H. Phee, W. Rodgers, and K. M. Coggeshall (2001)
Mol. Cell. Biol. 21, 8615-8625
   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