Regulation of c-Fes tyrosine kinase and biological activities by N- terminal coiled-coil oligomerization domains

Haiyun Cheng, Jim A Rogers, Nancy A. Dunham, Thomas E. Smithgall

Research output: Contribution to journalArticle

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Abstract

The cytoplasmic protein-tyrosine kinase Fes has been implicated in cytokine signal transduction, hematopoiesis, and embryonic development. Previous work from our laboratory has shown that active Fes exists as a large oligomeric complex in vitro. However, when Fes is expressed in mammalian cells, its kinase activity is tightly repressed. The Fes unique N-terminal sequence has two regions with strong homology to coiled-coil-forming domains often found in oligomeric proteins. Here we show that disruption or deletion of the first coiled-coil domain upregulates Fes tyrosine kinase and transforming activities in Rat-2 fibroblasts and enhances Fes differentiation-inducing activity in myeloid leukemia cells. Conversely, expression of a Fes truncation mutant consisting only of the unique N- terminal domain interfered with Rat-2 fibroblast transformation by an activated Fes mutant, suggesting that oligomerization is essential for Fes activation in vivo. Coexpression with the Fes N-terminal region did not affect the transforming activity of v-Src in Rat-2 cells, arguing against a nonspecific suppressive effect. Taken together, these findings suggest a model in which Fes activation may involve coiled-coil-mediated interconversion of monomeric and oligomeric forms of the kinase. Mutation of the first coiled-coil domain may activate Fes by disturbing intramolecular coiled-coil interaction, allowing for oligomerization via the second coiled- coil domain. Deletion of the second coiled-coil domain blocks fibroblast transformation by an activated form of c-Fes, consistent with this model. These results provide the first evidence for regulation of a nonreceptor protein-tyrosine kinase by coiled-coil domains.

Original languageEnglish (US)
Pages (from-to)8335-8343
Number of pages9
JournalMolecular and cellular biology
Volume19
Issue number12
DOIs
StatePublished - Jan 1 1999

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Proto-Oncogene Proteins c-fes
Protein-Tyrosine Kinases
Fibroblasts
Phosphotransferases
Myeloid Leukemia
Hematopoiesis
Myeloid Cells
Embryonic Development
Signal Transduction
Up-Regulation
Cytokines
Mutation
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Regulation of c-Fes tyrosine kinase and biological activities by N- terminal coiled-coil oligomerization domains. / Cheng, Haiyun; Rogers, Jim A; Dunham, Nancy A.; Smithgall, Thomas E.

In: Molecular and cellular biology, Vol. 19, No. 12, 01.01.1999, p. 8335-8343.

Research output: Contribution to journalArticle

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