Genetic aberrations not only cause of cancer. Protein imbalances within cells leading cause.

proteinA new study published in the journal Oncogene has demonstrated that cancer is not only caused by genetic aberrations but can also be caused by protein imbalances within cells.

The collaborative study involving the University of Leeds and the University of Texas focused on the metabolic pathway called the  “Akt pathway,” a signalling pathway within cells that drives cancer formation and the spread of cancers through the body.

The Akt pathway is activated by a cell wall bound receptor (FGFR2) which switches on a signalling protein allowing the cell to multiply.  The study analyzed isolated cancer cells and found that  “Akt pathway” could be activated without genetic modifications. Two proteins; Plcγ1 (pronounced “plc-gamma-1”) and Grb2 (pronounced “grab-2”), compete for binding to FGFR2. The relative concentration of these proteins will dictate which one binds. When Plcγ1 prevails, it triggers the Akt pathway. An imbalance in the amount of the two proteins can lead to cell proliferation and cancer formation. The researchers used a mouse model to determine that Grb2 depletion results in the development of multiple tumours in the vicinity of a primary tumour, indicating that protein imbalance can have a role in metastasis, the spread of a cancer through the body. This makes sense because Plcγ1 can play a role in increasing cell movement.

“There has been huge investment in sequencing the human genome with the idea that if we get all the relevant genetic information we can predict whether you have a predisposition to cancer and, ultimately, use a precision medicine-based approach to develop a therapeutic approach. Our study demonstrates that genetic screening alone is not enough,” said Lead author Professor John Ladbury, Dean of the University of Leeds’ Faculty of Biological Sciences and Professor of Mechanistic Biology.

“This competition for binding to the receptor represents an unexpected way in which cancer can occur”, said Dr Zahra Timsah, University Academic Fellow at the University of Leeds’ School of Molecular and Cellular Biology lead researcher on the study.” We found that in cells where Grb2 is depleted, FGFR2 was vulnerable to Plcγ1 binding and that this triggered uncontrolled proliferation. Increasing the amount of Grb2 rescued this effect to maintain normal FGFR2 activity. What we think is happening is that under normal conditions the two proteins compete fairly evenly and that the Plcγ1 binding events allow useful cell housekeeping. When the proteins get imbalanced, Plcγ1 can get out of control.”


Z Timsah, Z Ahmed, C Ivan, J Berrout, M Gagea, Y Zhou, G N A Pena, Xin Hu, C Vallien, C V Kingsley, Y Lu, J F Hancock, J Liu, A B Gladden, G B Mills, G Lopez-Berestein, M-C Hung, A K Sood, M Bogdanov, J E Ladbury. Grb2 depletion under non-stimulated conditions inhibits PTEN, promotes Akt-induced tumor formation and contributes to poor prognosis in ovarian cancer. Oncogene, 2015; DOI:10.1038/onc.2015.279

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