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An Identity Crisis for fps/fes: Oncogene or Tumor Suppressor?

¹ Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute and Departments of ² Pathology and Molecular Medicine and ³ Biochemistry, Queen's University, Kingston, Ontario, Canada and ⁴ Molecular Oncology Group, McGill University Health Center, Montreal, Quebec, Canada

Requests for reprints: Peter A. Greer, Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute, Botterell Hall, Room A309, Kingston, Ontario, Canada K7L 3N6. Phone: 613-533-2813; Fax: 613-533-6830; E-mail: greerp{at}post.queensu.ca.

Fps/Fes proteins were among the first members of the protein tyrosine kinase family to be characterized as dominant-acting oncoproteins. Addition of retroviral GAG sequences or other experimentally induced mutations activated the latent transforming potential of Fps/Fes. However, activating mutations in fps/fes had not been found in human tumors until recently, when mutational analysis of a panel of colorectal cancers identified four somatic mutations in sequences encoding the Fps/Fes kinase domain. Here, we report biochemical and theoretical structural analysis demonstrating that three of these mutations result in inactivation, not activation, of Fps/Fes, whereas the fourth mutation compromised in vivo activity. These results did not concur with a classic dominant-acting oncogenic role for fps/fes involving activating somatic mutations but instead raised the possibility that inactivating fps/fes mutations might promote tumor progression in vivo. Consistent with this, we observed that tumor onset in a mouse model of breast epithelial cancer occurred earlier in mice targeted with either null or kinase-inactivating fps/fes mutations. Furthermore, a fps/fes transgene restored normal tumor onset kinetics in targeted fps/fes null mice. These data suggest a novel and unexpected tumor suppressor role for Fps/Fes in epithelial cells.

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