'W' mutant forms of the Fms receptor tyrosine kinase act in a dominant manner to suppress CSF-1 dependent cellular transformation.
Point mutations in highly conserved amino acid residues in the catalytic domain of the Kit receptor tyrosine kinase (RTK) are responsible for the coat color, fertility and hematopoietic defects of mice bearing mutant alleles at the dominant white-spotting (W) locus. The dominant nature of structural Kit mutations suggests that expression of other kinase-defective RTKs might also specifically interfere with signal transduction by normal receptors. To test this possibility, we have investigated the functional consequences of introducing analogous mutations into the RTK encoded by the c-fms proto-oncogene. Both Fms37 (glu582-->lys) and Fms42 (asp776-->asn) mutant proteins, corresponding to the strongly dominant-negative W37 and W42 mutant c-kit alleles, had undetectable in vitro kinase activity and were unable to transform Rat-2 fibroblasts in the presence of exogenous CSF-1. Moreover, expression of Fms37 or Fms42 proteins in Rat-2 cells specifically inhibited anchorage-independent growth mediated by the normal Fms receptor in the presence of exogenous CSF-1 and conferred a dominant loss of Fms-associated PI3-kinase activity on CSF-1 stimulation. Mutant RTKs, bearing point substitutions identical to those present in mild or severe W mutants, may provide a generally applicable strategy for inducing dominant loss of function defects in RTK-mediated signalling pathways.
Division of Molecular and Developmental Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada.
A D
AD
Reith
C
C
Ellis
N
N
Maroc
T
T
Pawson
A
A
Bernstein
P
P
Dubreuil
D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D051381:Rats; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000187:drug effects / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D013329:Structure-Activity Relationship
D011956:Receptors, Cell Surface; D016173:Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor