Haphazard activation of secondary signaling pathways may fuel cancer's genesis

When found at abnormally high concentrations, two proteins implicated in many human cancers have the potential to spur indiscriminate biochemical signaling inside cells, chemists at Harvard University have found.

Their finding may expand scientists' current understanding of oncogenesis -- that cancer arises when an oncoprotein becomes overactive, ramping up the biochemical pathways that it normally activates -- suggesting that an important additional mechanism could be the inappropriate activation of numerous secondary pathways.

"Our data offer a new way to think about cancer, adding to the current paradigm," says Gavin MacBeath, an assistant professor of chemistry and chemical biology in Harvard's Faculty of Arts and Sciences and co-author of a paper published in the journal Nature. "We present the hypothesis that an important component of oncogenesis is the ability of proteins to turn on alternative, secondary signaling pathways when overexpressed, rather than simply upregulating primary pathways."

MacBeath and colleagues studied the four human ErbB receptors, which set in motion widely studied cellular processes including cell migration, adhesion, growth and death. These receptors span the cell membrane; the external portion binds free growth factors, creating biochemical signals propagated inside the cell.

Each ErbB receptor has multiple intracellular binding sites where proteins can dock, but MacBeath's group found that only two of the four ErbB proteins, known as EGFR and ErbB2, become dramatically more "promiscuous" -- able to recruit and activate a large number of different signaling proteins -- when present at high concentrations.

"These two promiscuous ErbB proteins are known to be overactive in many human cancers, suggesting that their ability to turn on rampant signaling may contribute to their high oncogenic potential," MacBeath says. "This newfound link may also offer alternative strategies for therapeutic intervention. Many of today's cancer pharmaceuticals work by targeting individual receptors such as EGFR and ErbB2. Our work suggests that new drugs could target critical secondary pathways that are inappropriately activated by promiscuous proteins."

The researchers studied interactions between signaling proteins and the ErbB receptors using a protein microarray technique developed by MacBeath in 2000, when he was a research fellow in Harvard's Bauer Center for Genomic Research. This method can rapidly and simultaneously assess the strength of interactions among tens of thousands of proteins genome-wide. The current research analyzed the interactions between 159 proteins and 33 binding sites on the four ErbB receptors. The scientists looked not only at whether a given protein-receptor pair interacted, but also how strongly.