An identity crisis for fps/fes : Oncogene or tumor suppressor?

• Published in: Cancer research (Chicago, Ill.) Vol. 65; no. 9; pp. 3518 - 3522
• Main Authors: SANGRAR, Waheed, ZIRGNIBL, Ralph A, YAN GAO, MULLER, William J, ZONGCHAO JIA, GREER, Peter A
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-05-2005
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Enzyme Activation; Female; Gene Silencing; Genes, Tumor Suppressor; Mammary Neoplasms, Experimental - enzymology; Mammary Neoplasms, Experimental - genetics; Medical sciences; Mice; Mice, Knockout; Mice, Transgenic; Models, Molecular; Mutation; Oncogenes; Pharmacology. Drug treatments; Protein Conformation; Protein-Tyrosine Kinases - chemistry; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-fes; Tumors; Onc gene; Crisis; Tumor suppressor gene
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-04-3468

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.