Discovery May Aid Development of Anti-Cancer Drugs

Baylor College of Medicine researchers have identified a protein called hepatocyte growth factor-regulated tyrosine kinase substrate, or HRS, as a regulator of response to growth factors.

The HRS protein accomplishes this by controlling how many receptors in a cell are available to receive those chemical signals.

Because HRS regulates cell proliferation, it could be a target for the development of anti-cancer drugs, said Dr. Hugo Bellen, professor in the departments of molecular and human genetics and cell biology at Baylor College of Medicine, in whose lab the finding was made.

In a report first published in the Jan. 25 issue of the journal Cell, graduate student Tom Lloyd in Dr. Bellen’s lab noted that one way in which cells regulate growth and other responses to chemical messages is to seal the receptors to such messages into small bubbles or vesicles that then fuse into a larger bubble or endosome where their fates are determined. The receptors may be recycled back to the cell surface or they may be tagged for degradation and destruction in another cellular area called the lysosome, thus reducing the number of receptors available to receive a particular message.

"Signaling needs to stop at a certain time," said Dr. Bellen, who is also a Howard Hughes Medical Institute investigator. "The cell needs to take care of this because the process cannot go on indefinitely. For example, you don’t want growth to continue indefinitely because if it does, you will get cancer."

Dr. Bellen and his colleagues discovered that HRS is the protein that controls a crucial step in which the receptor on the cell’s membrane is inverted into small vesicles or bubbles. These multivesicular endosomes take the receptors to the lysosome for destruction.

Studying the process in Drosophila, or fruit flies, Lloyd and his colleagues found mutant flies that lacked a functional form of HRS. Under electron microscopes, they found that the flies had abnormally large endosomes, indicating that without functional HRS, the insects could not form the multivesicular bodies that go on to the lysosome where the growth signal receptor is degraded.

"If you remove the HRS, all the signals continue, which in humans could result in over proliferation and cancer," said Dr. Bellen. "If you over express the gene that causes production of HRS, or stimulate the protein, it then digests the signals. You can thus modulate how a cell receives a signal."

Capitalizing on this fact might make it possible to develop drugs that could modify the signals that can result in malignant growth, he said.

The other authors on this study are Richard Atkinson, Mark Wu, Giusy Pennetta and Yi Zhou.

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©2006 Texas Medical Center

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