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PLoS By Category | Recent
PLoS Articles
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Hematology - Molecular Biology - Oncology
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Short Stat5-Interacting Peptide Derived from Phospholipase C-ß3 Inhibits Hematopoietic Cell Proliferation and Myeloid Differentiation
Published:
Tuesday, September 20, 2011
Author:
Hiroki Yasudo et al.
by Hiroki Yasudo, Tomoaki Ando, Wenbin Xiao, Yuko Kawakami, Toshiaki Kawakami
Constitutive activation of the transcription factor Stat5 in hematopoietic stem/progenitor cells leads to various hematopoietic malignancies including myeloproliferative neoplasm (MPN). Our recent study found that phospholipase C (PLC)-ß3 is a novel tumor suppressor involved in MPN, lymphoma and other tumors. Stat5 activity is negatively regulated by the SH2 domain-containing protein phosphatase SHP-1 in a PLC-ß3-dependent manner. PLC-ß3 can form the multimolecular SPS complex together with SHP-1 and Stat5. The close physical proximity of SHP-1 and Stat5 brought about by interacting with the C-terminal segment of PLC-ß3 (PLC-ß3-CT) accelerates SHP-1-mediated dephosphorylation of Stat5. Here we identify the minimal sequences within PLC-ß3-CT required for its tumor suppressor function. Two of the three Stat5-binding noncontiguous regions, one of which also binds SHP-1, substantially inhibited in vitro proliferation of Ba/F3 cells. Surprisingly, an 11-residue Stat5-binding peptide (residues 988-998) suppressed Stat5 activity in Ba/F3 cells and in vivo proliferation and myeloid differentiation of hematopoietic stem/progenitor cells. Therefore, this study further defines PLC-ß3-CT as the Stat5- and SHP-1-binding domain by identifying minimal functional sequences of PLC-ß3 for its tumor suppressor function and implies their potential utility in the control of hematopoietic malignancies.
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