Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 539-549
The Receptor Protein Tyrosine Phosphatase, PTP-RO, Is Upregulated
During Megakaryocyte Differentiation and Is Associated With the c-Kit
Receptor
Yoshitaka Taniguchi,
Roanna London,
Karin Schinkmann,
Shuxian Jiang, and
Hava Avraham
From the Division of Experimental Medicine, Beth Israel Deaconess
Medical Center, Harvard Institutes of Medicine, Boston, MA.
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 PTP
and is related to the homotypically adhering
and µ 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.