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Membrane proteins and TGF-alpha/EGFR: a role in lung cancer?

Institution: University of California, San Francisco
Investigator(s): Wen Shi, Ph.D.
Award Cycle: 1999 (Cycle 8) Grant #: 8FT-0033 Award: $40,436
Subject Area: Cancer
Award Type: Postdoctoral Fellowship Awards
Abstracts

Initial Award Abstract
Communication between different parts of the body is required for proper function. This communication is precisely controlled and its deregulation results in many diseases. It has been well established that long-term cigarette smoking causes a number of illnesses, including lung cancer. Among all the possible causes, cigarette smoking (either first hand or second hand) accounts for 85%-90% of lung cancer cases. However, much remains to be discovered regarding how the components in tobacco cause the deregulation of bodily communication that leads to cancerous transformation of lung tissue.

In many cases, cell communication is mediated by small protein molecules called growth factors. Protein growth factors are important regulators of the growth and function of cells in the lung. One of the important growth factors is transforming growth factor alpha (TGF-), which is the growth factor I will investigate. TGF- can change a cell's behavior, making it grow or specialize, by binding to another unique protein (a receptor called EGFR) on the cells' surface. When a cell no longer responds to growth factors or overproduces growth factors and/or their receptors, this cell may undergo uncontrolled growth that results in tumor formation. Strong evidence suggests that TGF- is involved in both the normal growth of lung epithelial cells and its cancerous transformation. The over-production of TGF- and related growth factors can initiate cancerous transformation from normal lung cells to malignant state. Interestingly, cancerous lung cells also produce elevated levels of TGF-.

Even though we believe that TGF- plays important roles in both normal and disease states of lung tissue, much remains unknown about how TGF- participates in regulating the cancerous transformation of normal lung cells. The change in cell behavior caused by TGF- and EGFR is a complicated process. This proposal is aimed at characterizing two proteins (CD9 and hRho) that are associated with TGF-/EGFR and are believed to be important regulators in TGF-/EGFR signaling pathways. We plan to conduct a series of biochemical studies designed to accomplish two aims: (1) To investigate the consequences of CD9/TGF- binding on cell morphology, cell adhesion and cell polarization, all of which undergo changes during cancerous transformation; (2) to characterize the structural and biochemical bases of the interaction between hRho and TGF-/EGFR in order to learn more about how this interaction regulates cell growth and differentiation. Research on how TGF- affects lung cell behavior in both normal and disease states will help us to better understand the role of TGF- in the progression of lung cancer. Ultimately, this may help us design new ways to prevent and control the lung cancer in the future.

Final Report
TGF-a signaling molecule, plays important roles in both normal and disease states of lung tissue such as lung cancer. For example, cancerous lung cells produce elevated levels of TGF-. The over-production of TGF- and related growth factors can initiate cancerous transformation from normal lung cells to malignant state. However, much remains unknown about how TGF- participates in regulating these processes. The change in cell behavior caused by interaction between TGF- and its sensing molecule at the cell surface (receptor)-EGFR, is a complicated processs and involves other proteins' participation. The objective of this research project is aimed at characterizing the roles of two TGF-/EGFR associated proteins, CD9 and Rhomboid, in regulating in TGF-/EGFR signaling pathways.

In the past year, we have demonstrated that CD9, a protein with four transmembrane domains, can significantly enhance the TGF- expression in our in-vitro systems. We have further demonstrated that the increased expression level of TGF-are in part due to CD9 preventing TM TGF- to be removed from the cell surface by specialized enzymes. In addition, we have shown that CD9 also affect TGF-'s ability to regulate cell growth through EGFR. Interestingly, the regulation can be very different (activating or inhibiting), depending on how TGF- and EGFR are being presented. We have demonstrated that co-expression of CD9 with TGF- can also influence epithelial morphology, which leads to more cancerous phenotype. These results were summarized in the publication in Journal of Cell Biology.

In the following year, we plan to further examine of how TGF- and its receptor influence several important cell behavior, such as polarized transport of selective molecules throughout the cells. We also plan to further our studies in animal models, to understand how tumor formation and metastasis can be influenced by these TGF- associated molecules. We believe research on how TGF- affecting lung cell behavior in both normal and disease states will help us to better understand the role of TGF- in the progression of lung cancer. Ultimately, this may help us design new ways to prevent and control the lung cancer in the future.
Publications

The tetraspanin CD9 associates with transmembrane TGF-alpha and regulates TGF-alpha induced EGF receptor activation and cell proliferation
Periodical: Journal of Cell Biology Index Medicus:
Authors: Shi W, Fan H, Shum L, Derynck R ART
Yr: 2000 Vol: 148 Nbr: 3 Abs: Pg: 591-601