May 28, 2004

Protein acts as double agent for cancer growth, suppression

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Robert Coffey, M.D.

Protein acts as double agent for cancer growth, suppression

It’s almost like discovering that a spy is a double agent.

Vanderbilt-Ingram Cancer Center scientists have found a surprising link between two important cell signal pathways involved in numerous biologic processes from cell fate decisions during development to cancer, especially colorectal cancer.

And the protein at the heart of the finding, known as Naked 2 (NKD2), in some cases seems to contribute to cell growth, which can fuel the development and progression of cancer, while in other cases the same protein actually helps shut down signals that lead to cancer.

The Vanderbilt team recently reported in the Proceedings of the National Academy of Sciences their “unexpected” observation from cell culture experiments that a protein known as NKD2 (NKD2) escorts a growth factor, transforming growth factor alpha (TGFa), to its cell-surface docking point with the epidermal growth factor receptor (EGFr).

This transport enables TGFa to bind to EGFr, activating it and sending growth signals to the cell nucleus; this cell signal pathway is known to be important in the development and progression of cancers.

NKD2’s previously known function is as a key player in a separate signaling pathway known as WNT, which is also involved in colorectal cancer. Ironically, in this case, the cell produces NKD2 to stop cancer development. It does so when the WNT pathway goes awry and a cancer-promoting protein called beta-catenin escapes normal cell defenses and makes it to the nucleus to start a cascade of gene activation that leads to cancer.

NKD2 binds another protein in the pathway; this, in turn, allows the normal cell defenses to stop and eliminate beta-catenin before it gets to the nucleus and, as lead author Robert Coffey, M.D., puts it, “all hell breaks loose.”

“The cell says, in effect, ‘I’ve got to shut this pathway off,’ and sends out NKD2 to do that,” Coffey explained.

“So what we’ve observed is a totally unexpected and surprising convergence between these two important signal pathways, EGFr-related events and WNT signaling.”

The observation reveals contradictory consequences for NKD2 activity – in the case of the WNT pathway, NKD2 interferes with the development and progression of cancer, whereas by escorting TGFa to its receptor, it contributes to cell growth.

It also raises an interesting question – which Coffey’s team will explore further – about whether the two pathways compete for NKD2’s attention. That is, does its interaction with TGFa prevent it from doing its job to shut down WNT signaling?

The research was funded by the National Cancer Institute, including support from VICC’s Mouse Models of Human Cancer Consortium Grant (MMHCC) and its GI Cancer Specialized Program of Research Excellence (SPORE) grant.

In addition to Coffey, authors include Cunxi Li, Jeffrey L. Franklin, Ramona Graves-Deal, W. Gray Jerome, and Zheng Cao, representing the departments of Medicine, Cell and Developmental Biology and Pathology. Coffey is Ingram Professor of Cancer Research and director of the GI SPORE and the MMHCC.