FKBP12 Is a Negative Regulator of Transforming Growth Factor-β Receptor Internalization*
- From the Thoracic Disease Research Unit and the Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905
Abstract
Transforming growth factor-β (TGF-β) family polypeptides regulate cell growth and differentiation by binding to single pass serine/threonine kinases referred to as TGF-β type I and II receptors. Although interaction screens have shown that the immunophilin FKBP12 interacts with TGF-β type I receptors, the role of FKBP12 in TGF-β receptor action is presently unclear. Using a chimeric TGF-β receptor system, we have shown a specific enhancement of internalization when FKBP12 binding to the type I receptor was prevented with rapamycin. Moreover, although earlier studies demonstrated that type II receptor kinase activity was required for optimal internalization in mesenchymal cells, we found that rapamycin functioned downstream of the type II receptor kinase. Thus, rather than modulating TGF-β signaling, our data suggest a novel role for FKBP12 as a negative regulator of TGF-β receptor endocytosis.
Footnotes
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↵* This work was supported by National Institutes of Health Grants GM54200 and GM55816 and by the Mayo Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ To whom correspondence should be addressed: Guggenheim 6, Mayo Clinic, Rochester, MN 55905. Tel.: 507-284-5717; Fax: 507-284-4521; E-mail: leof.edward@mayo.edu.
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↵2 D. Yao, J. J. E. Doré, Jr., and E. B. Leof, manuscript in preparation.
- Abbreviations:
- TGF-β
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transforming growth factor-β
- TGF-βR
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TGF-β receptor
- GM-CSF
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granulocyte/macrophage colony-stimulating factor
- PAI-1
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plasminogen activator inhibitor-1
- EGF
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epidermal growth factor
- FBS
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fetal bovine serum
- DMEM
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Dulbecco's modified Eagle's medium
- PBS
-
phosphate-buffered saline
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- Received September 29, 1999.
- Revision received January 13, 2000.
- The American Society for Biochemistry and Molecular Biology, Inc.
