Researchers at the University of Texas MD Anderson Cancer Center in Houston have uncovered a classic case of an angel on one shoulder and a devil on the other. In this case, the “shoulder” is fibroblast growth factor receptor-2 (FGFR2) found on the cell membrane; the “angel” is growth factor receptor bound protein 2 (Grb2); and the “devil” is phospholipase Cy1 (Plcy1). Grb2 and Plcy1 compete to bind with FGFR2, and whichever wins has drastically different results for the cell. If Grb2 binds FGFR2, the cell is held in a neutral state, ready to be acted on by a growth factor to stimulate cell signaling. Grb2 shields FGFR2 from being acted on by Plcy1, but if Plcy1 has the opportunity to bind FGFR2, the risk for the cell to become metastatic increases. The protein that wins is determined by the relative concentrations of the two proteins in the cell: “in cells with depleted Grb2 concentration, Plcy1 gets on the receptor, increasing cellular motility–equipping cells to move, escape the tumor, invade other tissue, and spread,” says John Ladbury, Ph.D., professor of Biochemistry and Molecular Biology.
These findings, detailed in a 2012 paper from Cell, may lead to a new, reliable marker for cancer cell metastasis risk and influence the choice of cancer treatment. At least five cancer types–lung, ovarian, kidney, breast, and colon–show a correlation between over-expression of Plcy1 with under-expression of Grb2 and an increased risk of metastasis. The reverse holds true: high Grb2 with low Plcy1 correlate to a low risk of cancer metastasis. This means that if a patient with, for example, lung cancer has their expression levels of Grb2 and Plcy1 checked, and the patient has high Plcy1 expression with low Grb2 expression, the patient may develop metastatic lung cancer. Their clinician may then decide that chemotherapy is necessary in addition to surgery in order to combat metastasis.
Read other BioNews Texas article related to protein research:
[feed url=”http://bionews-tx.com/news/news-tags/protein/feed” number=”5″ ]
Researchers used a series of cell lines for their experiments, leaving the cells in homeostasis without growth factor stimulation. In this neutral state, both Grb2 and Ply1 are able to bind the same site of FGFR2, with the binding of Grb2 blocking the binding of Plcy1. Each protein binds FGFR2 with its own SH3 domain, and neither of these domains is used in normal growth factor signaling. Normal growth factor signaling is accomplished by a growth factor (e.g. fibroblast growth factor-2) binding to FGFR2’s outer portion, triggering FGFR2’s inner portion to send along signals to internal actuating proteins. “That a protein can find a receptor using its SH3 domain is an entirely new idea,” said Landbury, “There’s a lot of background activity in cells, just to keep the ticking over and in the past we’ve kind of ignored what’s happening there. Now we’ve shown that if these background activities are perturbed, they can lead to cancer.”
Further studies by the group will find the prognostic levels of Grb2, Plcy1, and FGFR2 in cancer cells, as well as identify other receptors’ potential to bind the SH3 domain of proteins to maintain homeostasis in cells.
Co-authors with Ladbury and first author Zahra Timsah, a graduate student in The University of Texas Graduate School of Biomedical Sciences, a joint program of MD Anderson and The University of Texas Health Science Center at Houston (UTHealth), are Zamal Ahmed, Ph.D., Chi-Chuan Lin, Ph.D., Fernando Melo, Ph.D., Loren Stagg, Ph.D., Paul Leonard, Ph.D, and Prince Jeyabal, Ph.D., all in the Department of Biochemistry and Molecular Biology; Jonathan Berrout, Ph.D., and Roger O’Neil, Ph.D., in the Department of Integrative Biology and Pharmacology at UTHealth, and Mikhail Bogdanov, Ph.D., of the Department of Biochemistry and Molecular Biology at UTHealth.
This research was funded by the G. Harold and Leila Y. Mathers Charitable Foundation and a grant from the U.S. National Institutes of Health (DK070950).