Advisory Committee Chair
Chenbei Chang
Advisory Committee Members
Stuart Frank
Louis Justement
Fang-Tsyr Lin
Rosa Serra
Document Type
Dissertation
Date of Award
2006
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Growth factor signals often regulate similar cellular processes both during embryogenesis and in adult homeostasis. Stringent control of these signals ensures proper embryonic development and correct cell physiology in mature individuals. Recently, a family of two members of Tomoregulin (or transmembrane protein with epidermal growth factor-like and two follistatin domains [TMEFF]) was found to interact with transforming growth factor-β (TGF-β) and ErbB signaling pathways, both of which are implicated in development and in cancer biology in the adult. The function as well as the mechanisms of TMEFFs in modulating these two signals has not been elucidated in detail. In this dissertation, I investigate the activities of TMEFFs in modulating signaling by the of TGF-β and ErbB pathways in a vertebrate model and in mammalian cell culture, respectively. In the first part, I showed that TMEFF1 selectively inhibits nodal but not activin signals in early Xenopus embryos through direct interaction with the nodal coreceptor Cripto. Accordingly, Cripto rescues the inhibition of the nodal signaling by TMEFF1 in Xenopus ectodermal explants. Furthermore, I showed that the Cripto-FRL1- Cryptic (CFC) domain in Cripto, which is essential for its binding to the type I nodal receptor ALK4, is also important for its interaction with TMEFF1. This study demonstrates for the first time that nodal signaling can be regulated by a novel mechanism of blocking the Cripto coreceptor. In the second part, I uncovered a novel association between both TMEFFs and all four ErbB family members in iv coimmunoprecipitation assays. The epidermal growth factor-like domain of TMEFF1 was dispensable for its association with ErbB4, suggesting that TMEFFs bind ErbB receptors in a manner unlike orthodox ErbB ligands. Functional analyses of the consequence of TMEFF/ErbB interaction revealed that TMEFFs do not affect ErbB signaling in tumor cell lines despite the direct physical association. TMEFFs may thus have subtle effects on ErbB-regulated processes in a cell type- and/or environmentdependent manner. In summary, my work identifies direct associations of TMEFFs with Cripto and ErbB receptor tyrosine kinases and suggests novel roles for TMEFFs in modulating TGF-β and ErbB signaling during embryonic development and tumorigenesis.
Recommended Citation
Harms, Paul William, "Modulation Of Cell Signaling By Tomoregulins In Embryogenesis And Cancer" (2006). All ETDs from UAB. 3713.
https://digitalcommons.library.uab.edu/etd-collection/3713