Originally published In Press as doi:10.1074/jbc.M413223200 on January 18, 2005
J. Biol. Chem., Vol. 280, Issue 11, 10870-10876, March 18, 2005
Type I Transforming Growth Factor 
Receptor Binds to and Activates Phosphatidylinositol 3-Kinase*
Jae Youn Yi,
Incheol Shin, and
Carlos L. Arteaga
From the
Departments of Medicine and Cancer Biology and Breast Cancer Program, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
We have examined the interaction of transforming growth factor (TGF)
receptors with phosphatidylinositol 3-(PI3) kinase in epithelial cells. In COS7 cells, treatment with TGF increased PI3 kinase activity as measured by the ability of p85-associated immune complexes to phosphorylate inositides in vitro. Both type I and type II TGF receptors (TR) associated with p85, but the association of TRII appeared to be constitutive. The interaction of TRI with p85 was induced by treatment with TGF. The receptor association with PI3 kinase was not direct as 35S-labeled rabbit reticulocyte p85 did not couple with fusion proteins containing type I and type II receptors. A kinase-dead, dominant-negative mutant of TRII blocked ligand-induced p85-TRI association and PI3 kinase activity. In TRI-null R1B cells, TGF did not stimulate PI3 kinase activity. This stimulation was restored upon reconstitution of TRI by transfection. In R1B and NMuMG epithelial cells, overexpression of a dominant active mutant form of TRI markedly enhanced ligand-independent PI3 kinase activity, which was blocked by the addition of the TRI kinase inhibitor LY580276, suggesting a causal link between TRI function and PI3 kinase. Overexpressed Smad7 also prevented ligand-induced PI3 kinase activity. Taken together, these data suggest that 1) TGF receptors can indirectly associate with p85, 2) both receptors are required for ligand-induced PI3 kinase activation, and 3) the activated TRI serine-threonine kinase can potently induce PI3 kinase activity.
Received for publication, November 23, 2004
, and in revised form, January 13, 2005.
* This work was supported by National Institutes of Health Grant R01 CA62212 (to C. L. A.), Breast Cancer Specialized Program of Research Excellence (SPORE) Grant P50 CA98131, and Vanderbilt-Ingram Comprehensive Cancer Center Support Grant CA68485. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed: Division of Oncology, Vanderbilt University Medical Center, 2220 Pierce Ave., 777 PRB, Nashville, TN 37232-6307. E-mail: carlos.arteaga{at}vanderbilt.edu.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
J. H. Kwak, S. I. Kim, J. K. Kim, and M. E. Choi
BAT3 Interacts with Transforming Growth Factor-{beta} (TGF-{beta}) Receptors and Enhances TGF-{beta}1-induced Type I Collagen Expression in Mesangial Cells
J. Biol. Chem.,
July 11, 2008;
283(28):
19816 - 19825.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Wang, L. Yang, J. Yang, K. Kuropatwinski, W. Wang, X.-Q. Liu, J. Hauser, and M. G. Brattain
Transforming Growth Factor {beta} Induces Apoptosis through Repressing the Phosphoinositide 3-Kinase/AKT/Survivin Pathway in Colon Cancer Cells
Cancer Res.,
May 1, 2008;
68(9):
3152 - 3160.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. I. Kim, J. H. Kwak, L. Wang, and M. E. Choi
Protein Phosphatase 2A Is a Negative Regulator of Transforming Growth Factor-{beta}1-induced TAK1 Activation in Mesangial Cells
J. Biol. Chem.,
April 18, 2008;
283(16):
10753 - 10763.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Meran, D. W. Thomas, P. Stephens, S. Enoch, J. Martin, R. Steadman, and A. O. Phillips
Hyaluronan Facilitates Transforming Growth Factor-{beta}1-mediated Fibroblast Proliferation
J. Biol. Chem.,
March 7, 2008;
283(10):
6530 - 6545.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. M. Martin, J. A. Buckenberger, J. Jiang, G. E. Malana, D. L. Knoell, D. S. Feldman, and T. S. Elton
TGF-beta1 stimulates human AT1 receptor expression in lung fibroblasts by cross talk between the Smad, p38 MAPK, JNK, and PI3K signaling pathways
Am J Physiol Lung Cell Mol Physiol,
September 1, 2007;
293(3):
L790 - L799.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Lamouille and R. Derynck
Cell size and invasion in TGF-{beta} induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway
J. Cell Biol.,
July 24, 2007;
178(3):
437 - 451.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Xie, M. B. Sukkar, R. Issa, N. M. Khorasani, and K. F. Chung
Mechanisms of induction of airway smooth muscle hyperplasia by transforming growth factor-beta
Am J Physiol Lung Cell Mol Physiol,
July 1, 2007;
293(1):
L245 - L253.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Sturrock, T. P. Huecksteadt, K. Norman, K. Sanders, T. M. Murphy, P. Chitano, K. Wilson, J. R. Hoidal, and T. P. Kennedy
Nox4 mediates TGF-beta1-induced retinoblastoma protein phosphorylation, proliferation, and hypertrophy in human airway smooth muscle cells
Am J Physiol Lung Cell Mol Physiol,
June 1, 2007;
292(6):
L1543 - L1555.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P.-P. Kuang, X.-H. Zhang, C. B. Rich, J. A. Foster, M. Subramanian, and R. H. Goldstein
Activation of elastin transcription by transforming growth factor-beta in human lung fibroblasts
Am J Physiol Lung Cell Mol Physiol,
April 1, 2007;
292(4):
L944 - L952.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Yang, Y. Zhang, Y. Li, Z. Wu, and D. Zhu
Myostatin Induces Cyclin D1 Degradation to Cause Cell Cycle Arrest through a Phosphatidylinositol 3-Kinase/AKT/GSK-3beta Pathway and Is Antagonized by Insulin-like Growth Factor 1
J. Biol. Chem.,
February 9, 2007;
282(6):
3799 - 3808.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Oganesian, S. Au, J. A. Horst, L. C. Holzhausen, A. J. Macy, J. M. Pace, and P. Bornstein
The NH2-terminal Propeptide of Type I Procollagen Acts Intracellularly to Modulate Cell Function
J. Biol. Chem.,
December 15, 2006;
281(50):
38507 - 38518.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Kato, H. Yuan, Z.-G. Xu, L. Lanting, S.-L. Li, M. Wang, M. C.-T. Hu, M. A. Reddy, and R. Natarajan
Role of the Akt/FoxO3a Pathway in TGF-beta1-Mediated Mesangial Cell Dysfunction: A Novel Mechanism Related to Diabetic Kidney Disease
J. Am. Soc. Nephrol.,
December 1, 2006;
17(12):
3325 - 3335.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Seoane
Escaping from the TGF{beta} anti-proliferative control
Carcinogenesis,
November 1, 2006;
27(11):
2148 - 2156.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. E. Wang, I. Shin, F. Y. Wu, D. B. Friedman, and C. L. Arteaga
HER2/Neu (ErbB2) Signaling to Rac1-Pak1 Is Temporally and Spatially Modulated by Transforming Growth Factor {beta}
Cancer Res.,
October 1, 2006;
66(19):
9591 - 9600.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Biswas, T. L. Criswell, S. E. Wang, and C. L. Arteaga
Inhibition of Transforming Growth Factor-{beta} Signaling in Human Cancer: Targeting a Tumor Suppressor Network as a Therapeutic Strategy.
Clin. Cancer Res.,
July 15, 2006;
12(14):
4142 - 4146.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Varon, F. Tatin, V. Moreau, E. Van Obberghen-Schilling, S. Fernandez-Sauze, E. Reuzeau, I. Kramer, and E. Genot
Transforming Growth Factor {beta} Induces Rosettes of Podosomes in Primary Aortic Endothelial Cells.
Mol. Cell. Biol.,
May 1, 2006;
26(9):
3582 - 3594.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Medici, E. D. Hay, and D. A. Goodenough
Cooperation between Snail and LEF-1 Transcription Factors Is Essential for TGF-beta1-induced Epithelial-Mesenchymal Transition
Mol. Biol. Cell,
April 1, 2006;
17(4):
1871 - 1879.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. R. A. Johnson, J. K. Burgess, Q. Ge, M. Poniris, S. Boustany, S. M. Twigg, and J. L. Black
Connective Tissue Growth Factor Induces Extracellular Matrix in Asthmatic Airway Smooth Muscle
Am. J. Respir. Crit. Care Med.,
January 1, 2006;
173(1):
32 - 41.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. C. Wilkes, H. Mitchell, S. G. Penheiter, J. J. Dore, K. Suzuki, M. Edens, D. K. Sharma, R. E. Pagano, and E. B. Leof
Transforming Growth Factor-{beta} Activation of Phosphatidylinositol 3-Kinase Is Independent of Smad2 and Smad3 and Regulates Fibroblast Responses via p21-Activated Kinase-2
Cancer Res.,
November 15, 2005;
65(22):
10431 - 10440.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Vogelmann, M.-D. Nguyen-tat, K. Giehl, G. Adler, D. Wedlich, and A. Menke
TGF{beta}-induced downregulation of E-cadherin-based cell-cell adhesion depends on PI3-kinase and PTEN
J. Cell Sci.,
October 15, 2005;
118(20):
4901 - 4912.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Levy and C. S. Hill
Smad4 Dependency Defines Two Classes of Transforming Growth Factor {beta} (TGF-{beta}) Target Genes and Distinguishes TGF-{beta}-Induced Epithelial-Mesenchymal Transition from Its Antiproliferative and Migratory Responses
Mol. Cell. Biol.,
September 15, 2005;
25(18):
8108 - 8125.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Moustakas and C.-H. Heldin
Non-Smad TGF-{beta} signals
J. Cell Sci.,
August 15, 2005;
118(16):
3573 - 3584.
[Abstract]
[Full Text]
[PDF]
|
|
|
Copyright © 2005 by the American Society for Biochemistry and Molecular Biology.
