The receptor protein tyrosine phosphatase, PTP-RO, is upregulated during megakaryocyte differentiation and Is associated with the c-Kit receptor.
We have recently isolated a cDNA encoding a novel human receptor-type tyrosine phosphatase, termed PTP-RO (for a protein tyrosine phosphatase receptor omicron), from 5-fluorouracil-treated murine bone marrow cells. PTP-RO is a human homologue of murine PTPlambda and is related to the homotypically adhering kappa and mu receptor-type tyrosine phosphatases. PTP-RO is expressed in human megakaryocytic cell lines, primary bone marrow megakaryocytes, and stem cells. PTP-RO mRNA and protein expression are upregulated upon phorbol 12-myristate 13-acetate (PMA) treatment of the megakaryocytic cell lines CMS, CMK, and Dami. To elucidate the function of PTP-RO in megakaryocytic cells and its potential involvement in the stem cell factor (SCF)/c-Kit receptor pathway, COS-7 and 293 cells were cotransfected with the cDNAs of both the c-Kit tyrosine kinase receptor and PTP-RO. PTP-RO was found to be associated with the c-Kit receptor in these transfected cells and the SCF/Kit ligand induced a rapid tyrosine phosphorylation of PTP-RO. Interestingly, these transfected cells demonstrated a decrease in their proliferative response to the SCF/Kit ligand. In addition, we assessed the association of PTP-RO with c-Kit in vivo. The results demonstrated that PTP-RO associates with c-Kit but not with the tyrosine kinase receptor FGF-R and that PTP-RO is tyrosine-phosphorylated after SCF stimulation of Mo7e and CMK cells. Antisense oligonucleotides directed against PTP-RO mRNA sequences significantly inhibited megakaryocyte progenitor proliferation. Therefore, these data show that the novel tyrosine kinase phosphatase PTP-RO is involved in megakaryocytopoiesis and that its function is mediated by the SCF/c-Kit pathway.
Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, MA, USA.
Y
Y
Taniguchi
R
R
London
K
K
Schinkmann
S
S
Jiang
H
H
Avraham
D000293:Adolescent; D000818:Animals; D019556:COS Cells; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006410:Hematopoiesis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology; D008533:Megakaryocytes / Q000166:cytology* / Q000201:enzymology; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D019089:Stem Cell Factor / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators; D014162:Transfection; D014407:Tumor Cells, Cultured; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D015820:Cadherins; D003598:Cytoskeletal Proteins; D016376:Oligonucleotides, Antisense; D011993:Recombinant Fusion Proteins; D019089:Stem Cell Factor; D015534:Trans-Activators; D051176:beta Catenin; D019009:Proto-Oncogene Proteins c-kit; C516888:PTPRO protein, human; C516868:PTPRU protein, human; D017027:Protein Tyrosine Phosphatases; C516890:Ptpro protein, mouse; C516869:Ptpru protein, mouse; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D013755:Tetradecanoylphorbol Acetate