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

Mol. Cell. Biol. 22 (13): 4750-4759

Copyright © 2002 by the American Society for Microbiology. All rights reserved.

Internalization-Dependent and -Independent Requirements for Transforming Growth Factor ß Receptor Signaling via the Smad Pathway

Sumedha G. Penheiter, Hugh Mitchell, Nandor Garamszegi, Maryanne Edens, Jules J. E. Doré, Jr., and Edward B. Leof*

Thoracic Diseases Research Unit and Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905

Received for publication 2 October 2001. Revision received 8 November 2001. Accepted for publication 18 March 2002.

Abstract: Members of the transforming growth factor ß (TGF-ß) family of proteins signal through cell surface transmembrane serine/threonine protein kinases known as type I and type II receptors. The TGF-ß signal is extended through phosphorylation of receptor-associated Smad proteins by the type I receptor. Although numerous investigations have established the sequence of events in TGF-ß receptor (TGF-ßR) activation, none have examined the role of the endocytic pathway in initiation and/or maintenance of the signaling response. In this study we investigated whether TGF-ßR internalization modulates type I receptor activation, the formation of a functional receptor/Smad/SARA complex, Smad2/3 phosphorylation or nuclear translocation, and TGF-ß-dependent reporter gene activity. Our data provide evidence that, whereas type I receptor phosphorylation and association of SARA and Smad2 with the TGF-ßR complex take place independently of clathrin lattice formation, Smad2 or Smad3 activation and downstream signaling only occur after endocytic vesicle formation. Thus, TGF-ßR endocytosis is not simply a way to dampen the signaling response but instead is required to propagate signaling via the Smad pathway.


* Corresponding author. Mailing address: Stabile 858, Mayo Clinic, Rochester, MN 55905. Phone: (507) 284-5717. Fax: (507) 284-4521. E-mail: leof.edward{at}mayo.edu.



THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Retromer maintains basolateral distribution of the type II TGF-{beta} receptor via the recycling endosome.
X. Yin, S. J. Murphy, M. C. Wilkes, Y. Ji, and E. B. Leof (2013)
Mol. Biol. Cell 24, 2285-2298
   Abstract »    Full Text »    PDF »
Coated Pit-mediated Endocytosis of the Type I Transforming Growth Factor-{beta} (TGF-{beta}) Receptor Depends on a Di-leucine Family Signal and Is Not Required for Signaling.
K. E. Shapira, A. Gross, M. Ehrlich, and Y. I. Henis (2012)
J. Biol. Chem. 287, 26876-26889
   Abstract »    Full Text »    PDF »
ERBIN is a new SARA-interacting protein: competition between SARA and SMAD2 and SMAD3 for binding to ERBIN.
G. Sflomos, E. Kostaras, E. Panopoulou, N. Pappas, A. Kyrkou, A. S. Politou, T. Fotsis, and C. Murphy (2011)
J. Cell Sci. 124, 3209-3222
   Abstract »    Full Text »    PDF »
Type II Transforming Growth Factor-{beta} Receptor Recycling Is Dependent upon the Clathrin Adaptor Protein Dab2.
S. G. Penheiter, R. Deep Singh, C. E. Repellin, M. C. Wilkes, M. Edens, P. H. Howe, R. E. Pagano, and E. B. Leof (2010)
Mol. Biol. Cell 21, 4009-4019
   Abstract »    Full Text »    PDF »
Annexin A1 regulates TGF-{beta} signaling and promotes metastasis formation of basal-like breast cancer cells.
M. de Graauw, M. H. van Miltenburg, M. K. Schmidt, C. Pont, R. Lalai, J. Kartopawiro, E. Pardali, S. E. Le Devedec, V. T. Smit, A. van der Wal, et al. (2010)
PNAS 107, 6340-6345
   Abstract »    Full Text »    PDF »
Role of SARA (SMAD Anchor for Receptor Activation) in Maintenance of Epithelial Cell Phenotype.
C. E. Runyan, T. Hayashida, S. Hubchak, J. F. Curley, and H. W. Schnaper (2009)
J. Biol. Chem. 284, 25181-25189
   Abstract »    Full Text »    PDF »
Rab5-mediated endocytosis of activin is not required for gene activation or long-range signalling in Xenopus.
A. I. Hagemann, X. Xu, O. Nentwich, M. Hyvonen, and J. C. Smith (2009)
Development 136, 2803-2813
   Abstract »    Full Text »    PDF »
Inhibitors of clathrin-dependent endocytosis enhance TGF{beta} signaling and responses.
C.-L. Chen, W.-H. Hou, I-H. Liu, G. Hsiao, S. S. Huang, and J. S. Huang (2009)
J. Cell Sci. 122, 1863-1871
   Abstract »    Full Text »    PDF »
Extracellular Matrix-Induced Gene Expression in Human Breast Cancer Cells.
N. Garamszegi, S. P. Garamszegi, L. A. Shehadeh, and S. P. Scully (2009)
Mol. Cancer Res. 7, 319-329
   Abstract »    Full Text »    PDF »
Specific Activation of Mitogen-activated Protein Kinase by Transforming Growth Factor-{beta} Receptors in Lipid Rafts Is Required for Epithelial Cell Plasticity.
W. Zuo and Y.-G. Chen (2009)
Mol. Biol. Cell 20, 1020-1029
   Abstract »    Full Text »    PDF »
Endocytosis of the Type III Transforming Growth Factor-{beta} (TGF-{beta}) Receptor through the Clathrin-independent/Lipid Raft Pathway Regulates TGF-{beta} Signaling and Receptor Down-regulation.
E. C. Finger, N. Y. Lee, H.-j. You, and G. C. Blobe (2008)
J. Biol. Chem. 283, 34808-34818
   Abstract »    Full Text »    PDF »
Cripto Localizes Nodal at the Limiting Membrane of Early Endosomes.
M.-H. Blanchet, J. A. Le Good, V. Oorschot, S. Baflast, G. Minchiotti, J. Klumperman, and D. B. Constam (2008)
Science Signaling 1, ra13
   Abstract »    Full Text »    PDF »
Integration of Transforming Growth Factor {beta} and RAS Signaling Silences a RAB5 Guanine Nucleotide Exchange Factor and Enhances Growth Factor-Directed Cell Migration.
H. Hu, M. Milstein, J. M. Bliss, M. Thai, G. Malhotra, L. C. Huynh, and J. Colicelli (2008)
Mol. Cell. Biol. 28, 1573-1583
   Abstract »    Full Text »    PDF »
Requirement for the Dynein Light Chain km23-1 in a Smad2-dependent Transforming Growth Factor-beta Signaling Pathway.
Q. Jin, W. Ding, and K. M. Mulder (2007)
J. Biol. Chem. 282, 19122-19132
   Abstract »    Full Text »    PDF »
Transforming Growth Factor {beta} Signaling via Ras in Mesenchymal Cells Requires p21-Activated Kinase 2 for Extracellular Signal-Regulated Kinase-Dependent Transcriptional Responses.
K. Suzuki, M. C. Wilkes, N. Garamszegi, M. Edens, and E. B. Leof (2007)
Cancer Res. 67, 3673-3682
   Abstract »    Full Text »    PDF »
Endofin, a FYVE Domain Protein, Interacts with Smad4 and Facilitates Transforming Growth Factor-beta Signaling.
Y.-G. Chen, Z. Wang, J. Ma, L. Zhang, and Z. Lu (2007)
J. Biol. Chem. 282, 9688-9695
   Abstract »    Full Text »    PDF »
CELL BIOLOGY: Sara Splits the Signal..
J. A. Knoblich (2006)
Science 314, 1094-1096
   Abstract »    Full Text »    PDF »
Different Routes of Bone Morphogenic Protein (BMP) Receptor Endocytosis Influence BMP Signaling.
A. Hartung, K. Bitton-Worms, M. M. Rechtman, V. Wenzel, J. H. Boergermann, S. Hassel, Y. I. Henis, and P. Knaus (2006)
Mol. Cell. Biol. 26, 7791-7805
   Abstract »    Full Text »    PDF »
Transforming Growth Factor beta Activation of c-Abl Is Independent of Receptor Internalization and Regulated by Phosphatidylinositol 3-Kinase and PAK2 in Mesenchymal Cultures.
M. C. Wilkes and E. B. Leof (2006)
J. Biol. Chem. 281, 27846-27854
   Abstract »    Full Text »    PDF »
Role of transforming growth factor-beta in hematologic malignancies.
M. Dong and G. C. Blobe (2006)
Blood 107, 4589-4596
   Abstract »    Full Text »    PDF »
FKBP12 functions as an adaptor of the Smad7-Smurf1 complex on activin type I receptor..
T Yamaguchi, A Kurisaki, N Yamakawa, K Minakuchi, and H Sugino (2006)
J. Mol. Endocrinol. 36, 569-579
   Abstract »    Full Text »    PDF »
Transforming Growth Factor-{beta} Activation of Phosphatidylinositol 3-Kinase Is Independent of Smad2 and Smad3 and Regulates Fibroblast Responses via p21-Activated Kinase-2.
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 (2005)
Cancer Res. 65, 10431-10440
   Abstract »    Full Text »    PDF »
Transforming Growth Factor-{beta} Suppresses Nonmetastatic Colon Cancer through Smad4 and Adaptor Protein ELF at an Early Stage of Tumorigenesis.
Y. Tang, V. Katuri, R. Srinivasan, F. Fogt, R. Redman, G. Anand, A. Said, T. Fishbein, M. Zasloff, E. P. Reddy, et al. (2005)
Cancer Res. 65, 4228-4237
   Abstract »    Full Text »    PDF »
Role of Transforming Growth Factor Beta in Human Cancer.
R. L. Elliott and G. C. Blobe (2005)
J. Clin. Oncol. 23, 2078-2093
   Abstract »    Full Text »    PDF »
The Role of Internalization in Transforming Growth Factor {beta}1-induced Smad2 Association with Smad Anchor for Receptor Activation (SARA) and Smad2-dependent Signaling in Human Mesangial Cells.
C. E. Runyan, H. W. Schnaper, and A.-C. Poncelet (2005)
J. Biol. Chem. 280, 8300-8308
   Abstract »    Full Text »    PDF »
Inhibin Resistance Is Associated with Aggressive Tumorigenicity of Ovarian Cancer Cells.
M. D. Steller, T. J. Shaw, B. C. Vanderhyden, and J.-F. Ethier (2005)
Mol. Cancer Res. 3, 50-61
   Abstract »    Full Text »    PDF »
Zebrafish Dpr2 Inhibits Mesoderm Induction by Promoting Degradation of Nodal Receptors.
L. Zhang, H. Zhou, Y. Su, Z. Sun, H. Zhang, L. Zhang, Y. Zhang, Y. Ning, Y.-G. Chen, and A. Meng (2004)
Science 306, 114-117
   Abstract »    Full Text »    PDF »
Ligand-dependent and -independent Transforming Growth Factor-{beta} Receptor Recycling Regulated by Clathrin-mediated Endocytosis and Rab11.
H. Mitchell, A. Choudhury, R. E. Pagano, and E. B. Leof (2004)
Mol. Biol. Cell 15, 4166-4178
   Abstract »    Full Text »    PDF »
The Cell Fate Determinant Numb Interacts with EHD/Rme-1 Family Proteins and Has a Role in Endocytic Recycling.
C. A. Smith, S. E. Dho, J. Donaldson, U. Tepass, and C. J. McGlade (2004)
Mol. Biol. Cell 15, 3698-3708
   Abstract »    Full Text »    PDF »
Hyaluronan Regulates Transforming Growth Factor-{beta}1 Receptor Compartmentalization.
T. Ito, J. D. Williams, D. J. Fraser, and A. O. Phillips (2004)
J. Biol. Chem. 279, 25326-25332
   Abstract »    Full Text »    PDF »
Albumin endocytosis in endothelial cells induces TGF-{beta} receptor II signaling.
S. S. Siddiqui, Z. K. Siddiqui, and A. B. Malik (2004)
Am J Physiol Lung Cell Mol Physiol 286, L1016-L1026
   Abstract »    Full Text »    PDF »
Structural Basis for Endosomal Targeting by FYVE Domains.
A. Hayakawa, S. J. Hayes, D. C. Lawe, E. Sudharshan, R. Tuft, K. Fogarty, D. Lambright, and S. Corvera (2004)
J. Biol. Chem. 279, 5958-5966
   Abstract »    Full Text »    PDF »
Cell-Type-Specific Activation of PAK2 by Transforming Growth Factor {beta} Independent of Smad2 and Smad3.
M. C. Wilkes, S. J. Murphy, N. Garamszegi, and E. B. Leof (2003)
Mol. Cell. Biol. 23, 8878-8889
   Abstract »    Full Text »    PDF »
Stepwise formation of a SMAD activity gradient during dorsal-ventral patterning of the Drosophila embryo.
D. J. Sutherland, M. Li, X.-q. Liu, R. Stefancsik, and L. A. Raftery (2003)
Development 130, 5705-5716
   Abstract »    Full Text »    PDF »
Retrograde Gbb signaling through the Bmp type 2 receptor Wishful Thinking regulates systemic FMRFa expression in Drosophila.
G. Marques, T. E. Haerry, M. L. Crotty, M. Xue, B. Zhang, and M. B. O'Connor (2003)
Development 130, 5457-5470
   Abstract »    Full Text »    PDF »
Cellular growth inhibition by IGFBP-3 and TGF-{beta}1 requires LRP-1.
S. S. HUANG, T.-Y. LING, W.-F. TSENG, Y.-H. HUANG, F.-M. TANG, S. M. LEAL, and J. S. HUANG (2003)
FASEB J 17, 2068-2081
   Abstract »    Full Text »    PDF »
Insulin-like Growth Factor-I Inhibits Transcriptional Responses of Transforming Growth Factor-{beta} by Phosphatidylinositol 3-Kinase/Akt-dependent Suppression of the Activation of Smad3 but Not Smad2.
K. Song, S. C. Cornelius, M. Reiss, and D. Danielpour (2003)
J. Biol. Chem. 278, 38342-38351
   Abstract »    Full Text »    PDF »
{beta}-Arrestin 2 Mediates Endocytosis of Type III TGF-{beta} Receptor and Down-Regulation of Its Signaling.
W. Chen, K. C. Kirkbride, T. How, C. D. Nelson, J. Mo, J. P. Frederick, X.-F. Wang, R. J. Lefkowitz, and G. C. Blobe (2003)
Science 301, 1394-1397
   Abstract »    Full Text »    PDF »
TLP, a novel modulator of TGF-{beta} signaling, has opposite effects on Smad2- and Smad3-dependent signaling.
A. Felici, J. U. Wurthner, W. T. Parks, L. Ruh-yu Giam, M. Reiss, T. S. Karpova, J. G. McNally, and A. B. Roberts (2003)
EMBO J. 22, 4465-4477
   Abstract »    Full Text »    PDF »
Development and Characterization of DP-153, a Nontumorigenic Prostatic Cell Line That Undergoes Malignant Transformation by Expression of Dominant-negative Transforming Growth Factor {beta} Receptor Type II.
K. Song, S. C. Cornelius, and D. Danielpour (2003)
Cancer Res. 63, 4358-4367
   Abstract »    Full Text »    PDF »
Modulation of Transforming Growth Factor-beta (TGF-beta ) Signaling by Endogenous Sphingolipid Mediators.
M. Sato, M. Markiewicz, M. Yamanaka, A. Bielawska, C. Mao, L. M. Obeid, Y. A. Hannun, and M. Trojanowska (2003)
J. Biol. Chem. 278, 9276-9282
   Abstract »    Full Text »    PDF »
Regulation of ALK-1 Signaling by the Nuclear Receptor LXRbeta.
J. Mo, S. J. Fang, W. Chen, and G. C. Blobe (2002)
J. Biol. Chem. 277, 50788-50794
   Abstract »    Full Text »    PDF »
A Novel Transforming Growth Factor-beta Receptor-interacting Protein That Is Also a Light Chain of the Motor Protein Dynein.
Q. Tang, C. M. Staub, G. Gao, Q. Jin, Z. Wang, W. Ding, R. E. Aurigemma, and K. M. Mulder (2002)
Mol. Biol. Cell 13, 4484-4496
   Abstract »    Full Text »    PDF »
TGF{beta} receptor internalization into EEA1-enriched early endosomes: role in signaling to Smad2.
S. Hayes, A. Chawla, and S. Corvera (2002)
J. Cell Biol. 158, 1239-1249
   Abstract »    Full Text »    PDF »
Disabled-2 exhibits the properties of a cargo-selective endocytic clathrin adaptor.
S. K. Mishra, P. A. Keyel, M. J. Hawryluk, N. R. Agostinelli, S. C. Watkins, and L. M. Traub (2002)
EMBO J. 21, 4915-4926
   Abstract »    Full Text »    PDF »
From mono- to oligo-Smads: The heart of the matter in TGF-beta signal transduction.
A. Moustakas and C.-H. Heldin (2002)
Genes & Dev. 16, 1867-1871
   Full Text »    PDF »

To Advertise     Find Products


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