An identity crisis for fps/fes: oncogene or tumor suppressor?
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.
Sangrar
Waheed
W
Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
Zirgnibl
Ralph A
RA
Gao
Yan
Y
Muller
William J
WJ
Jia
Zongchao
Z
Greer
Peter A
PA
D000818:Animals; D004789:Enzyme Activation; D005260:Female; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008958:Models, Molecular; D009154:Mutation; D009857:Oncogenes; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051578:Proto-Oncogene Proteins c-fes
D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C496646:Fes protein, mouse; D051578:Proto-Oncogene Proteins c-fes