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J Biol Chem, Vol. 274, Issue 32, 22328-22336, August 6, 1999

Transforming Properties of the Huntingtin Interacting Protein 1/ Platelet-derived Growth Factor  Receptor Fusion Protein

Theodora S. Ross^§ and D. Gary Gilliland

From the  Division of Hematology/Oncology, Brigham and Women's Hospital and the ^§ Department of Adult Oncology, Dana-Farber Cancer Institute, and the  Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115

We have previously reported that the Huntingtin interacting protein 1 (HIP1) gene is fused to the platelet-derived growth factor  receptor (PDGFR) gene in a patient with chronic myelomonocytic leukemia. We now show that HIP1/PDGFR oligomerizes, is constitutively tyrosine-phosphorylated, and transforms the murine hematopoietic cell line, Ba/F3, to interleukin-3-independent growth. A kinase-inactive mutant is neither tyrosine-phosphorylated nor able to transform Ba/F3 cells. Oligomerization and kinase activation required the 55-amino acid carboxyl-terminal TALIN homology region but not the leucine zipper domain. Tyrosine phosphorylation of a 130-kDa protein and STAT5 correlates with transformation in cells expressing HIP1/PDGFR and related mutants. A deletion mutant fusion protein that contains only the TALIN homology region of HIP1 fused to PDGFR is incapable of transforming Ba/F3 cells and does not tyrosine-phosphorylate p130 or STAT5, although it is itself constitutively tyrosine-phosphorylated. We have also analyzed cells expressing Tyr  Phe mutants of HIP1/PDGFR in the known PDGFR SH2 docking sites and report that none of these sites are necessary for STAT5 activation, p130 phosphorylation, or Ba/F3 transformation. The correlation of factor-independent growth of hematopoietic cells with p130 and STAT5 phosphorylation/activation in both the HIP1/PDGFR Tyr  Phe and deletion mutational variants suggests that both STAT5 and p130 are important for transformation mediated by HIP1/PDGFR.

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