Hematopoietic Cell Phosphatase Negatively Regulates Erythropoietin-Induced Hemoglobinization in Erythroleukemic SKT6 Cells

Abstract

In an increasing number of hematopoietic cytokine receptor HCP function, inhibition of HCP expression by antisense oligonucleotides enhanced hemoglobinization, whereas the systems (T-cell receptor, B-cell receptor, and macrophage colony-stimulating factor, stem cell factor, interleukin-3, and enforced ectopic expression of wild-type (wt) HCP markedly inhibited EPO-induced globin expression and Stat5 activa-erythropoietin [EPO] receptors), inhibitory roles for the protein tyrosine phosphatase hematopoietic cell phosphatase tion. Based on these findings, epidermal growth factor (EGF) receptor/EPO receptor chimeras containing either the wt (HCP; SHPTP1, PTP1C, and SHP1) have been defined in proliferative signaling. However, evidence exists to suggest that EPO receptor cytoplasmic domain (EECA) or a derived HCP binding site mutant (EECA-Y429,431F) were expressed in HCP also may exert important effects on blood cell differentiation. To investigate possible roles for HCP during late ery-SKT6 cells, and their abilities to mediate differentiation were assayed. Each chimera supported EGF-induced hemoglo-throid differentiation, effects of manipulating HCP expression or recruitment on EPO-induced hemoglobinization in binization, but efficiencies for EECA-Y429,431F were enhanced 400% to 500%. Thus, these studies show a novel role erythroleukemic SKT6 cells have been investigated. No effects of EPO on levels of HCP, Syp, Stat5, the EPO receptor, for HCP as a negative regulator of EPO-induced erythroid differentiation. In normal erythroid progenitor cells, HCP or GATA-1 expression were observed during induced differentiation. However, the tyrosine phosphorylation of JAK2, may act to prevent premature commitment to terminal differentiation. In erythroleukemic SKT6 cells, this action also the EPO receptor, and Stat5 was efficiently activated, and HCP was observed to associate constitutively with the EPO may enforce mitogenesis. ᭧

A new high affinity binding site for suppressor of cytokine signaling‐3 on the erythropoietin receptor

“…Both pY429 and pY431 are phosphorylated after stimulation with Epo [34]. In Epo signal transduction, SHP1 has been reported to negatively regulate proliferation and differentiation of Ba/F3 or SKT6 cells [38,44]. Interestingly, we found a peptide encompassing the double phosphorylated tyrosine motif pY429pY431 to bind SOCS‐3 with a K d of 1.1 µ m , a ninefold higher affinity than determined for pY401.…”

Involvement of SHP‐1, a phosphotyrosine phosphatase, during myeloid cell differentiation in acute promyelocytic leukemia cell lines

“…The expression of SHP-1 was upregulated during macrophage differentiation of HL60 by phorbol 12-myristate 13-acetate (PMA) (12,13). On the other hand, overexpression of SHP-1 inhibited Epo-induced hemoglobinization in an erythroleukemia cell line (14). These results suggest that SHP-1 has a crucial role in hematopoietic cell differentiation.…”

Molecular mechanisms of thrombopoietin signaling

“…Once JAK kinases are active, their targets include (i) tyrosine residues within the receptor itself, creating phosphotyrosine (P‐Y) docking sites for signaling molecules that contain Shc homology (SH)2 or phosphotyrosine‐binding (PTB) motifs [1], (ii) molecules bound to the docking sites that promote cell survival and proliferation, including the signal transducers and activators of transcription (STATs) [3], phosphoinositol‐3‐kinase (PI3K) [4]; and the mitogen‐activated protein kinases (MAPKs), and (iii) and molecules bound to the receptor docking sites that limit cell signaling, including phosphatases such as SHP1 [5], SHIP1 [6] and PTEN [7] and suppressors of cytokine signaling (SOCS) [8]. Moreover, ligand engagement leads to receptor internalization and either recycling to the cell surface, or destruction [9], which also affect signaling.…”