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Blood, 15 July 2004, Vol. 104, No. 2, pp. 535-542. Prepublished online as a Blood First Edition Paper on March 30, 2004; DOI 10.1182/blood-2004-01-0169. This Article Full Text (PDF) All Versions of this Article: 2004-01-0169v1 104/2/535    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chen, J. Articles by Gilliland, D G Search for Related Content PubMed PubMed Citation Articles by Chen, J. Articles by Gilliland, D G Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 15, 2004 Accepted March 11, 2004 Positive and Negative Regulatory Roles of the WW-like Domain in TEL-PDGFR Transformation Jing Chen, Ifor R Williams, Jeffrey L Kutok, Nicole Duclos, Ema Anastasiadou, Shane C Masters, Haian Fu, and D G Gilliland* Howard Hughes Medical Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA Pathology, Emory University, Atlanta, GA, USA Pathology, Brigham & Women's Hospital, Boston, MA, USA Howard Hughes Medical Institute, Boston, MA, USA Pharmacology, Emory University, Atlanta, GA, USA * Corresponding author; email: ggilliland{at}rics.bwh.harvard.edu. TEL-PDGFR is expressed in chronic myelomonocytic leukemias associated with t(5;12)(q33;p13), and the fusion tyrosine kinase retains a conserved WW-like domain in the PDGFR autoinhibitory juxtamembrane region. Here we report that mutation of the two conserved tryptophan residues of the WW-like domain has opposing effects on TEL-PDGFR kinase activation. Alanine substitution of W593, essential for protein-protein interaction in the context of other WW domains, impaired TEL-PDGFR mediated transformation of hematopoietic cells due to inhibition of TEL-PDGFR kinase activity. In contrast, alanine substitution of W566, essential for structural integrity of WW domain in other contexts, had no effect on TEL-PDGFR activation and oncogenic activity. Surprisingly, however, the W566A mutation suppressed the W593A phenotype. Double mutant W566A/W593A was indistinguishable from the wildtype fusion protein with regard to kinase activity, ability to confer factor independent growth to Ba/F3 cells, or ability to induce a myeloproliferative disease in mice. Additional mutational analysis identified other substitutions within the WW-like domain in addition to W566A that could also suppress the W593A phenotype, including mutations predicted to diminish the autoinhibitory function of the juxtamembrane region. Therefore, the WW-like domain in the context of TEL-PDGFR may have both positive and negative regulatory roles in kinase activation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. H. Stover, J. Chen, B. H. Lee, J. Cools, E. McDowell, J. Adelsperger, D. Cullen, A. Coburn, S. A. Moore, R. Okabe, et al. The small molecule tyrosine kinase inhibitor AMN107 inhibits TEL-PDGFR{beta} and FIP1L1-PDGFR{alpha} in vitro and in vivo Blood, November 1, 2005; 106(9): 3206 - 3213. [Abstract] [Full Text] [PDF] J. Chen, I. R. Williams, B. H. Lee, N. Duclos, B. J. P. Huntly, D. J. Donoghue, and D. G. Gilliland Constitutively activated FGFR3 mutants signal through PLC{gamma}-dependent and -independent pathways for hematopoietic transformation Blood, July 1, 2005; 106(1): 328 - 337. [Abstract] [Full Text] [PDF]

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