VOLUME 12, NUMBER 11 • DECEMBER 8, 2000

Rockefeller roots

The biology of the crk oncogene has deep roots at Rockefeller, nearly spanning the 100-year history of the institution and encompassing disciplines ranging from virology to biochemistry to immunology.

In 1911 Peyton Rous discovered a tumor agent, later called the Rous Sarcoma Virus (RSV), that transmitted cancer in chickens. Rous would later receive the Nobel Prize in Physiology or Medicine for this discovery. In 1931, one of Rous’s colleagues, James Murphy, proposed that the tumor-inducing agent was a "transmissible mutagen," whose mode of activity was to induce permanent mutations in the host cells that resulted in cancer.

By the early 1970s, virologist Hidesaburo Hanafusa showed that RSV contains a gene (called src for sarcoma) that produces a protein necessary for cancer. Removing the gene prevented the virus from inducing cancer.

In 1988, Hanafusa and his co-workers identified the crk oncogene from another cancer-causing chicken virus, CT10 (chicken tumor virus 10) avian sarcoma virus. The researchers found that Crk, the protein produced by the oncogene, has a unique structure: It is made up of two special molecular structures, known as SH2 and SH3, which are responsible for the virus’s cancer-causing abilities. SH2 and SH3 have also been found in the proteins made by many human oncogenes.

Hanafusa’s lab discovered that SH2 and SH3 act as subcellular switchboards, coupling proteins sending and receiving messages within a cell. These signal transduction pathways, somewhat like telephone lines, are the way molecules within a cell communicate with one another to regulate such important functions as cell growth and differentiation.

In the early 1990s, Hanafusa collaborated with other Rockefeller laboratories, including those headed by Professor John Kuriyan, an HHMI investigator, and Associate Professor David Cowburn, to provide a detailed structural understanding of how these modular domains interact. And in 1997, Kuriyan’s lab provided the first three-dimensional crystal structure of Hck, a protein related to Crk.

With the identification of a novel biological role for crk in phagocytosis, the stage is now set for continued investigation of this important gene.