Researchers Propose Drugs to Shut Down Cancer Promoting Signaling Molecules

Gab2 performs a number of signaling roles in normal cells throughout the body, and it is usually switched off when it is not required. Genomically, Gab2 operates downstream of a major breast cancer oncogene, HER2, the target of the drug Herceptin.

In the current study, published in the August 7, 2008, online edition of The EMBO Journal, the investigators added important details that explain how Gab2 slips out of control and triggers cancerous cell proliferation.

Normally Gab2 functions through an association with another protein called Grb2. When the cell wants to turn off Gab2 signaling, it uses proteins called 14-3-3 to break up the Gab2-Grb2 complex.

Senior author Dr. Roger Daly, a principal research fellow at the Garvan Institute of Medical Research, explained, "Gab2 performs a number of signaling roles in normal cells throughout the body, and is usually switched off when it is not needed. Our task has been to work out how the body switches off Gab2, so that we can mimic that process in abnormal cells. As Gab2 plays key roles in signaling systems that underpin both normal physiological responses and oncogenesis, it is very important to understand its control mechanisms.”

Summing up the current study, Dr. Daly said, "This binding partner is called 14-3-3, and is used to disable Gab2 in a number of cellular settings, when it is no longer needed. Our next step will be to obtain more structural information about how 14-3-3 shields Gab2. Once we know that, it should be possible to design drugs to combat Gab2-activated diseases in novel ways.”

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Garvan Institute of Medical Research