Cloning and Characterization of the Receptor for TPF (Tumor Promoting Factor), A Novel Angiogenic Factor
Abstract
The regulation of the Transforming Growth Factor-Beta (TGF-Beta) signaling pathway and its role in cancer is an area of intense research. We are investigating the regulatory role of casein kinase I (CKI) in the TGF-Beta signaling cascade. We have found that one family member inparticular, CKI epsilon, binds to all Smads and the cytoplasmic domains of the Type I and Type II receptors both in vitro and in vivo. The interaction of CKI epsilon with the Type I and Type II receptors is independent of TGF-beta ligand stimulation. However, the CKI epsilon/Smad interaction is transiently disrupted by TGF-beta stimulation, with complete disassociation by 2 hours. Since CKI epsilon is also a serine/threonine kinase, we examined in vitro phosphorylation of Smads and receptors by CKI epsilon and found that only the receptor activated Smads and the Type II Receptor are phosphorylated by CKI epsilon. In addition, we have mapped the CKIs phosphorylation sites of Smad3 to the MH1 domain and the linker region. Furthermore, in the absence of TGF-beta, transient overexpression of CKI epsilon dramatically reduces basal transcriptional reporter activity, but in the presence of ligand CKI epsilon increases TGF-beta mediated transcription. Finally, CKI epsilon is capable of significantly enhancing the transcriptional activity of smad3. Taken together, these observations provide exciting evidence for a functional role of CKI epsilon in the TGF-beta pathway, a pathway that has been shown to be involved in the development and progression of many different types of cancers.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2002
- Accession Number
- ADA410849
Entities
People
- David Waddell
- Nicole T. Liberati
- Xiao-Fan Wang
Organizations
- Duke University Hospital