The oncogenic fusion protein-tyrosine kinase ZNF198/fibroblast growth factor receptor-1 has signaling function comparable with interleukin-6 cytokine receptors

Heinz Baumann, Padmaja Kunapuli, Erin Tracy, John Kenneth Cowell

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

The reciprocal t(8;13) chromosome translocation results in a fusion gene (FUS) in which the N-terminal half of the zinc finger protein ZNF198 is combined with the cytoplasmic domain of the fibroblast growth factor receptor-1 (FGFR1). Expression of FUS is suggested to provide growth-promoting activity to myeloid cells similar to the activity of hematopoietic cytokine receptors. This study determined the specificity of FUS to activate signal transduction pathways. Because no tumor cell line expressing FUS was available, the mode of FUS action was identified in cells transiently and stably transfected with an expression vector for FUS. FUS acted as a constitutively active protein-tyrosine kinase and mediated phosphorylation of STAT1, 3, and 5 but not STAT4 and 6. The same specificity but lower activity was determined for normal FGFR1. STAT activation by FUS, similar to that by interleukin-6-type cytokines, promoted STAT-specific induction of genes. The functionality of FUS, as well as the relative recruitment of STAT isoforms, was determined by the dimerizing function of the zinc finger domain. Replacement of the ZNF198 portion by the Bcr portion as present in the t(8;22) translocation shifted the signaling toward a more prominent STAT5 activation. This study documents that both gene partners forming the fusion oncogene define the activity and the signaling specificity of the protein-tyrosine kinase of FGFR1.

Original languageEnglish (US)
Pages (from-to)16198-16208
Number of pages11
JournalJournal of Biological Chemistry
Volume278
Issue number18
DOIs
StatePublished - May 2 2003

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Receptor, Fibroblast Growth Factor, Type 1
Interleukin-6 Receptors
Cytokine Receptors
Gene Fusion
Protein-Tyrosine Kinases
Interleukin-6
Fusion reactions
Genes
Zinc Fingers
Oncogene Fusion
Zinc
Chromosomes, Human, Pair 13
Chromosomes, Human, Pair 8
Chemical activation
Myeloid Cells
Signal transduction
Tumor Cell Line
Phosphorylation
Transcriptional Activation
Chromosomes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

The oncogenic fusion protein-tyrosine kinase ZNF198/fibroblast growth factor receptor-1 has signaling function comparable with interleukin-6 cytokine receptors. / Baumann, Heinz; Kunapuli, Padmaja; Tracy, Erin; Cowell, John Kenneth.

In: Journal of Biological Chemistry, Vol. 278, No. 18, 02.05.2003, p. 16198-16208.

Research output: Contribution to journalArticle

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