Transforming properties of the Huntingtin interacting protein 1/platelet-derived growth factor beta receptor fusion protein

We have previously reported that the Huntingtin interacting protein 1 (HIP1 ) gene is fused to the platelet-derived growth factor beta receptor (PDGF b eta R) gene in a patient with chronic myelomonocytic leukemia. We now show that HIP1/PDGF beta R oligomerizes, is constitutively tyrosine-phosphorylat ed, and transforms the murine hematopoietic cell line, Ba/F3, to interleuki n-3-independent growth. A kinase-inactive mutant is neither tyrosine-phosph orylated nor able to transform Ba/F3 cells. Oligomerization and kinase acti vation required the 55-amino acid carboxyl-terminal TALIN homology region b ut not the leucine zipper domain. Tyrosine phosphorylation of a 130-kDa pro tein and STAT5 correlates with transformation in cells expressing HIP1/PDGF beta R and related mutants. A deletion mutant fusion protein that contains only the TALIN homology region of HIP1 fused to PDGF beta R is incapable o f transforming Ba/F3 cells and does not tyrosine-phosphorylate p130 or STAT 5, although it is itself constitutively tyrosine-phosphorylated. We have al so analyzed cells expressing Tyr --> Phe mutants of HIP1/PDGF beta R in the known PDGF beta R SH2 docking sites and report that none of these sites ar e necessary for STAT5 activation, p130 phosphorylation, or Ba/F3 transforma tion. The correlation of factor-independent growth of hematopoietic cells w ith p130 and STAT5 phosphorylation/activation in both the HIP1/ PDGF beta R Tyr --> Phe and deletion mutational variants suggests that both STAT5 and p130 are important for transformation mediated by HIP1/PDGF beta R.