Primary familial and congenital polycythemia (PFCP) is a disorder characterized by an increased number of erythrocytes despite normal blood oxygen pressure and a normal serum erythropoietin (EPO) level. Recent studies revealed that erythroid progenitor cells from certain individuals with PFCP express various forms of EPO receptor (EPOR) truncated at the terminal carboxyl site (EPOR-TTC(PFCP)). EPOR-TTC(PFCP) can transmit EPO-mediated proliferative signals more efficiently than can full-length EPOR (EPOR-F), at least partly because of defective recruitment of SHP-1 phosphatase to these receptors. In agreement with previous studies, Ba/F3 transfectants expressing EPOR-TTC(PFCP) showed higher proliferative responses to EPO. In those transfectants, we found that EPOR-TTC(PFCP) was expressed more abundantly on the cell surface than was EPOR-F. This tendency was confirmed by a transient-expression experiment using COS7 cells. Since expression levels of EPOR protein were not significantly different among these transfectants, differences in cell surface expression were likely dependent on post-translational mechanism(s). In addition to defective recruitment of SHP-1 to EPOR-TTC(PFCP), more efficient transport and expression on the cell surface appear to serve as mechanisms responsible for increased EPO-responsiveness of erythroid progenitor cells in PFCP.
"Also lacking is a proposed cytoplasmic binding motif for a BTRC E3 ubiquitin ligase . One hypothesis advanced for enhanced functional attributes of EPOR-T alleles has involved a prediction that such truncated receptor forms might be substantially compromised in internalization capacities (and consequently may reside persistently on the surface of erythroid progenitors) , , , , . Recent studies of mutated EPOR alleles in transfected gamma-2A and BaF3 cells also are consistent with this notion , . "
[Show abstract][Hide abstract] ABSTRACT: Erythropoietin (EPO) and its cell surface receptor (EPOR) are essential for erythropoiesis; can modulate non-erythroid target tissues; and have been reported to affect the progression of certain cancers. Basic studies of EPOR expression and trafficking, however, have been hindered by low-level EPOR occurrence, and the limited specificity of anti-EPOR antibodies. Consequently, these aspects of EPOR biology are not well defined, nor are actions of polycythemia- associated mutated EPOR alleles. Using novel rabbit monoclonal antibodies to intracellular, PY- activated and extracellular EPOR domains, the following properties of the endogenous hEPOR in erythroid progenitors first are unambiguously defined. 1) High- Mr EPOR forms become obviously expressed only when EPO is limited. 2) EPOR-68K plus -70K species sequentially accumulate, and EPOR-70K comprises an apparent cell surface EPOR population. 3) Brefeldin A, N-glycanase and associated analyses point to EPOR-68K as a core-glycosylated intracellular EPOR pool (of modest size). 4) In contrast to recent reports, EPOR inward trafficking is shown (in UT7epo cells, and primary proerythroblasts) to be sharply ligand-dependent. Beyond this, when C-terminal truncated hEPOR-T mutant alleles as harbored by polycythemia patients are co-expressed with the wild-type EPOR in EPO-dependent erythroid progenitors, several specific events become altered. First, EPOR-T alleles are persistently activated upon EPO- challenge, yet are also subject to apparent turn-over (to low-Mr EPOR products). Furthermore, during exponential cell growth EPOR-T species become both over-represented, and hyper-activated. Interestingly, EPOR-T expression also results in an EPO dose-dependent loss of endogenous wild-type EPOR's (and, therefore, a squelching of EPOR C-terminal- mediated negative feedback effects). New knowledge concerning regulated EPOR expression and trafficking therefore is provided, together with new insight into mechanisms via which mutated EPOR-T polycythemia alleles dysregulate the erythron. Notably, specific new tools also are characterized for studies of EPOR expression, activation, action and metabolism.
PLoS ONE 01/2012; 7(1):e29064. DOI:10.1371/journal.pone.0029064 · 3.23 Impact Factor
"In clinical investigations, hemodialysis patients that are hyporesponsive to the administration of recombinant human EPO has been attributed to active SHP-1 expression that leads to the dephosphorylation of STAT5 to impair EPO signaling (Akagi et al., 2004). Furthermore, primary familial and congential polycythemia, disorders that are characterized by elevated erythrocyte numbers with increased EPO-responsiveness of erythroid progenitor cells, have been shown to be a result of impaired modulation of the EPO receptor as a result of diminished expression and recruitment of SHP-1 (Furukawa et al., 1997; Wickrema et al., 1999a; Motohashi et al., 2001). Under normal conditions, SHP-1 can modulate and reduce EPO signaling through STAT5, the Jak2 kinase, and the inhibitory protein suppressor of cytokine signaling-1 (Minoo et al., 2004). "
[Show abstract][Hide abstract] ABSTRACT: Interest in the diverse biology of protein tyrosine phosphatases that are encoded by more than 100 genes in the human genome continues to grow at an accelerated pace. In particular, two cytoplasmic protein tyrosine phosphatases composed of two Src homology 2 (SH2) NH2-terminal domains and a C-terminal protein-tyrosine phosphatase domain referred to as SHP-1 and SHP-2 are known to govern a host of cellular functions. SHP-1 and SHP-2 modulate progenitor cell development, cellular growth, tissue inflammation, and cellular chemotaxis, but more recently the role of SHP-1 and SHP-2 to directly control cell survival involving oxidative stress pathways has come to light. SHP-1 and SHP-2 are fundamental for the function of several growth factor and metabolic pathways yielding far reaching implications for disease pathways and disorders such as diabetes, neurodegeneration, and cancer. Although SHP-1 and SHP-2 can employ similar or parallel cellular pathways, these proteins also clearly exert opposing effects upon downstream cellular cascades that affect early and late apoptotic programs. SHP-1 and SHP-2 modulate cellular signals that involve phosphatidylinositol 3-kinase, Akt, Janus kinase 2, signal transducer and activator of transcription proteins, mitogen-activating protein kinases, extracellular signal-related kinases, c-Jun-amino terminal kinases, and nuclear factor-kappaB. Our progressive understanding of the impact of SHP-1 and SHP-2 upon multiple cellular environments and organ systems should continue to facilitate the targeted development of treatments for a variety of disease entities.
Histology and histopathology 12/2007; 22(11):1251-67. · 2.10 Impact Factor
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