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Query: EC:2.7.10.2 (focal adhesion kinase)
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Interaction between erythropoietin (EPO) and its membrane receptor induces the proliferation and differentiation of erythroid progenitors. Targeted disruption of the EPO receptor (EPOR) gene have clearly demonstrated the importance of the EPO/EPOR system for definitive erythroid cell survival and proliferation; however, in vitro rescue experiments have revealed that it is not essential for differentiation. The three-dimensional structure of the EPOR has been determined, and a biologically active 20 amino acid peptide has been shown to cause dimerization of the extracellular domain of EPOR. EPO activates the JAK2-STAT5 pathway, and two tyrosine residues (Y343, Y401) in the cytoplasmic domain of EPOR are important for STAT5 activation. However, the physiologic role of STAT5 in erythroid cell proliferation and differentiation is still controversial. Mutations that result in C-terminal deletion of EPOR are frequently found in familial erythrocytosis. Hematopoietic cell phosphatase, which binds to the C-terminal region, could be involved in negative regulation of EPOR function.
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PMID:Physiology and function of the erythropoietin receptor. 966 55

ERYTHROPOIETIN (EPO): Erythropoietin (EPO) is a hormone that promotes the proliferation and differentiation of erythroid progenitor cells and regulates the number of erythrocytes in peripheral blood. EPO is produced mainly by the kidneys, and transcription of the EPO gene is promoted by a reduction in the oxygen concentration in the blood. The existence of EPO was suggested near the end of the 19th century by the discovery that hypoxia increases the production of red blood cells. EPO was identified as a serum factor in the 1950s, and in 1970 Miyake and coworkers succeeded in purifying it by using the urine of patients with aplastic anemia as a starting material. The human EPO gene was cloned in 1985 using a partial amino acid sequence from this purified EPO, and it is well known that recombinant EPO is currently used as a drug to treat anemia associated with chronic renal failure and other illnesses. ACTION OF EPO: When human bone marrow cells are cultured in a semisolid medium containing EPO, they form small erythroblast colonies in five to seven days, and by day 10 large erythroblast colonies appear that resemble fireworks ("burst" colonies). The original cells in the former colonies are called colony forming units-erythroid (CFU-E) or late-stage erythroblast progenitor cells and in the latter colonies they are called burst forming units-erythroid (BFU-E) or early-stage erythroblast progenitor cells. As shown in Figure 1, red blood cells are produced through differentiation from stem cells to BFU-E, CFU-E, and erythroblasts. Although EPO acts on both BFU-E and CFU-E cells, CFU-E cells show greater sensitivity to EPO, and other factors such as stem cell factor (SCF), interleukin (IL)-3, IL-4, and granulocyte macrophage colony-stimulating factor (GM-CSF) must be present together with EPO for BFU-E cell proliferation. In erythroblasts beyond the CFU-E stage, sensitivity to EPO decreases as the cells mature. THE EPO RECEPTOR AND THE CYTOKINE RECEPTOR FAMILY: The EPO receptor gene was cloned by D'Andrea and coworkers in 1989 from murine erythroleukemia cells [1]. It became clear that the EPO receptor belongs to the cytokine receptor family that comprises receptors for the various interleukins, GM-CSF, granulocyte colony-stimulating factor (G-CSF), growth hormone and prolactin. The special characteristic of this family of receptors is that they are switched on (i.e., the receptor is activated) and transduce signals to the interior of the cell by the formation of homo- or hetero-oligomers (dimers or trimers). Moreover, hetero-oligomers of these receptors share a common receptor subunit. As shown in Figure 2, the IL-3, IL-5 and GM-CSF receptors have a common &bgr; subunit, and their ligand specificity is determined by the &agr; subunit. In the same manner, the IL-6, LIF and oncostatin M (OSM) receptors all share gp130, which is the &bgr; subunit of the IL-6 receptor. The IL-2, IL-4 and IL-7 receptors all share the &ggr; subunit of the IL-2 receptor. All the above receptors are activated by the formation of hetero-oligomers, but the G-CSF receptor, EPO receptor, and growth hormone receptor are activated by the formation of homodimers of the same types of molecules [2]. We can see that groups of cytokines such as the interleukins that affect a relatively wide range of cells and have redundant biological activity create this redundancy through the common use of a single receptor subunit. On the other hand, EPO and G-CSF act with high specificity on a relatively limited range of cells, so it was probably unnecessary for their receptors to share one of the subunits. EPO RECEPTOR AND JAK2 KINASE: The signal for cellular proliferation and differentiation into erythroblasts is thought to originate at the EPO receptor. The cytoplasmic domain of the EPO receptor can be divided into two major regions. Roughly half of the cytoplasmic domain, the part lying nearest the plasma membrane, is required for generating the signals for proliferation and differentiation such as the induction of globin synthesis [3, 4]. The remaining half is not required for this signaling, and, conversely, it acts to dampen the signals. It is known that a tyrosine kinase called JAK2 associates with the region near the plasma membrane, undergoes autophosphorylation, and phosphorylates the EPO receptor, and a transcription factor called a STAT [5]. It is thought that JAK2 plays an important role in promoting cellular proliferation. The STAT is activated by the phosphorylation, and it then translocates to the nucleus, recognizes a specific base sequence in the promoter region of its target gene, and initiates transcription. At present, we know that the STAT whose activation is mediated by the EPO receptor is STAT5, and the target genes are CIS [6], which has an SH2 domain (a molecular structure that recognizes a phosphorylated tyrosine) and OSM [7], which is a pleiotropic cytokine. However, activation of STAT5 and activation of the target genes are not unique to the EPO receptor, and they also occur with the IL-2 and IL-3 receptors. Moreover, the JAK2 substrate that is directly linked to cellular proliferation is still unknown. At present, studies are under way to determine the transcription factors specific to EPO and their target genes, as well as the substrates of JAK2. RECEPTOR PHOSPHORYLATION AND CESSATION OF THE SIGNAL: On the other hand, tyrosine phosphorylation of the receptor is necessary at the cytoplasmic tail region far from the plasma membrane, and the signal transduction pathway that originates with this phosphorylated tyrosine and is mediated by proteins with SH2 domains becomes activated. First, a GTP/GDP exchange factor called SOS, which is mediated by Shc and Grb2, migrates to the plasma membrane and converts a ras protein to its GTP form. The activated ras protein then activates the Raf-MAP kinase kinase-MAP kinase cascade, and ultimately initiates the transcription of oncogenes such as c-fos and c-jun. An enzyme called PI3 kinase binds to the tyrosine phosphorylation site of the receptor and a second messenger is born. It is known that this pathway is a requirement for DNA synthesis in certain types of fibroblasts. However, these signal transduction pathways are not unique to the EPO receptor, and they are also activated by most growth factor receptors, so they are not necessarily required for EPO-induced proliferation. Conversely, the tyrosine phosphatase SH-PTP1 (also called HCP) that has an SH2 domain and is specific to blood cells associates with the tyrosine phosphorylation site of the receptor and promotes the dephosphorylation of JAK2. In other words, the role of SH-PTP1 is to stop generation of the signal [8]. Therefore, in mutations lacking this cytoplasmic tail region of the receptor far from the plasma membrane, the receptors do not undergo tyrosine phosphorylation, JAK2 activation continues for a longer period of time, and thus the signal is generated more efficiently. In fact, in one patient with a mild case of familial erythrocytosis a mutation was discovered in which the C-terminus of the EPO receptor was missing 70 amino acids [9]. This was a dominant genetic trait, and the patient's erythroblasts showed an increased sensitivity to EPO. In this family the impairment was not severe enough to be called an illness, and in fact it is said that this patient was proficient enough athletically to compete for a gold medal at the Olympics. More specifically, the reason that athletes undergo training at high altitudes is to boost EPO production because of the lower oxygen partial pressure, and this brings about the desired effect of sustained athletic capability due to a resultant increase in red blood cells. However, the same effect has occurred naturally in this athlete thanks to accelerated receptor capability.
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PMID:Physician Education: The Erythropoietin Receptor and Signal Transduction. 1038 12

SOCS3 (CIS3/JAB2) is an SH2-containing protein that binds to the activation loop of Janus kinases, inhibiting kinase activity, and thereby suppressing cytokine signaling. During embryonic development, SOCS3 is highly expressed in erythroid lineage cells and is Epo independent. Transgene-mediated expression blocks fetal erythropoiesis, resulting in embryonic lethality. SOCS3 deletion results in an embryonic lethality at 12-16 days associated with marked erythrocytosis. Moreover, the in vitro proliferative capacity of progenitors is greatly increased. SOCS3-deficient fetal liver stem cells can reconstitute hematopoiesis in lethally irradiated adults, indicating that its absence does not disturb bone marrow erythropoiesis. Reconstitution of lymphoid lineages in JAK3-deficient mice also occurs normally. The results demonstrate that SOCS3 is critical in negatively regulating fetal liver hematopoiesis.
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PMID:SOCS3 is essential in the regulation of fetal liver erythropoiesis. 1049 Jan 1

Several reports have suggested an interaction between the erythropoietin receptor (EpoR) and the shared signaling subunit (hbeta(c)) of the human granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 receptors, although the functional consequences of this interaction are unclear. We previously showed that in vivo expression of constitutively active extracellular (EC) mutants of hbeta(c) induces erythrocytosis and Epo independence of erythroid colony-forming units (CFU-E). This occurs despite an apparent requirement of these mutants for the GM-CSF receptor alpha-subunit (GMRalpha), which is not expressed in CFU-E. Here, we show that coexpression of hbeta(c) EC mutants and EpoR in BaF-B03 cells, which lack GMRalpha, results in factor-independent proliferation and JAK2 activation. Mutant receptors that cannot activate JAK2 fail to produce a functional interaction. As there is no detectable phosphorylation of hbeta(c) on intracellular tyrosine residues, EpoR displays constitutive tyrosine phosphorylation. These observations suggest that JAK2 activation mediates cross-talk between EC mutants of hbeta(c) and EpoR. The implications of these data are discussed as are our findings that activated hbeta(c) mutants can functionally interact with certain other cytokine receptors.
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PMID:Functional cross-talk between cytokine receptors revealed by activating mutations in the extracellular domain of the beta-subunit of the GM-CSF receptor. 1248 7

This minireview is an update of a 1997 review on erythropoietin (EPO) in this journal. EPO is a 30,400-dalton glycoprotein that regulates red cell production. In the human, EPO is produced by peritubular cells in the kidneys of the adult and in hepatocytes in the fetus. Small amounts of extra-renal EPO are produced by the liver in adult human subjects. EPO binds to an erythroid progenitor cell surface receptor that includes a p66 chain, and, when activated, the p66 protein becomes dimerized. EPO receptor activation induces a JAK2 tyrosine kinase, which leads to tyrosine phosphorylation of the EPO receptor and several proteins. EPO receptor binding leads to intracellular activation of the Ras/mitogen-activated kinase pathway, which is involved with cell proliferation, phosphatidylinositol 3-kinase, and STATS 1, 3, 5A, and 5B transcriptional factors. EPO acts primarily to rescue erythroid cells from apoptosis (programmed cell death) to increase their survival. EPO acts synergistically with several growth factors (SCF, GM-CSF, 1L-3, and IGF-1) to cause maturation and proliferation of erythroid progenitor cells (primarily colony-forming unit-E). Oxygen-dependent regulation of EPO gene expression is postulated to be controlled by a hypoxia-inducible transcription factor (HIF-1alpha). Hypoxia-inducible EPO production is controlled by a 50-bp hypoxia-inducible enhancer that is approximately 120 bp 3' to the polyadenylation site. Hypoxia signal transduction pathways involve kinases A and C, phospholipase A(2), and transcription factors ATF-1 and CREB-1. A model has been proposed for adenosine activation of EPO production that involves protein kinases A and C and the phospholipase A(2) pathway. Other effects of EPO include a hematocrit-independent, vasoconstriction-dependent hypertension, increased endothelin production, upregulation of tissue renin, change in vascular tissue prostaglandins production, stimulation of angiogenesis, and stimulation of endothelial and vascular smooth muscle cell proliferation. Recombinant human EPO (rHuEPO) is currently being used to treat patients with anemias associated with chronic renal failure, AIDS patients with anemia due to treatment with zidovudine, nonmyeloid malignancies in patients treated with chemotherapeutic agents, perioperative surgical patients, and autologous blood donation. A novel erythropoiesis-stimulating factor (NESP, darbepoetin) has been synthesized and when compared with rHuEPO, NESP has a higher carbohydrate content (52% vs 40%), a longer plasma half-life, the amino acid sequence differs from that of native human EPO at five positions, and has been reported to maintain hemoglobin levels just as effectively in patients with chronic renal failure as rHuEPO at less frequent dosing. The use of rHuEPO and darbepoetin to enhance athletic performance is officially banned by most sports-governing bodies because the excessive erythrocytosis can lead to increased thrombogenicity and can cause deep vein, coronary, and cerebral thromboses.
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PMID:Erythropoietin: physiology and pharmacology update. 1252 67

Myeloproliferative disorders are clonal haematopoietic stem cell malignancies characterized by independency or hypersensitivity of haematopoietic progenitors to numerous cytokines. The molecular basis of most myeloproliferative disorders is unknown. On the basis of the model of chronic myeloid leukaemia, it is expected that a constitutive tyrosine kinase activity could be at the origin of these diseases. Polycythaemia vera is an acquired myeloproliferative disorder, characterized by the presence of polycythaemia diversely associated with thrombocytosis, leukocytosis and splenomegaly. Polycythaemia vera progenitors are hypersensitive to erythropoietin and other cytokines. Here, we describe a clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (> 80%) polycythaemia vera patients. The mutation, a valine-to-phenylalanine substitution at amino acid position 617, leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model. As this mutation is also found in other myeloproliferative disorders, this unique mutation will permit a new molecular classification of these disorders and novel therapeutical approaches.
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PMID:A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. 1579 61

The analysis of rare chromosomal translocations in myeloproliferative disorders has highlighted the importance of aberrant tyrosine kinase signaling in the pathogenesis of these diseases. Here we have investigated samples from 679 patients and controls for the nonreceptor tyrosine kinase JAK2 V617F mutation. Of the 480 myeloproliferative disorder (MPD) samples, the proportion of positive cases per disease subtype was 30 (20%) of 152 for atypical or unclassified MPD, 2 of 134 (2%) for idiopathic hypereosinophilic syndrome, 58 of 72 (81%) for polycythemia vera, 24 of 59 (41%) essential thrombocythemia (ET), and 15 of 35 (43%) for idiopathic myelofibrosis. V617F was not identified in patients with systemic mastocytosis (n = 28), chronic or acute myeloid leukemia (n = 35), secondary erythrocytosis (n = 4), or healthy controls (n = 160). Homozygosity for V617F was seen in 43% of mutant samples and was closely correlated with chromosome 9p uniparental disomy. Homozygosity was significantly less common in ET compared with other MPD subtypes. In 53 cases analyzed, the median level of PRV1 expression was significantly higher in V617F-positive cases compared with cases without the mutation. We conclude that V617F is widespread in MPDs. Detection of this acquired mutation is likely to have a major impact on the way patients with MPD are diagnosed, as well as serving as an obvious target for signal transduction therapy.
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PMID:Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. 2741 38

Myeloproliferative disorders (MPD) represent a subcategory of hematological malignancies and are characterized by a stem cell-derived clonal proliferation of myeloid cells including erythrocytes, platelets, and leucocytes. Traditionally, the term 'MPD' included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis with myeloid metaplasia (MMM). At present, these four disorders are referred to as 'classic' MPD and are distinguished from a spectrum of other MPD-like clinicopathologic entities that are operationally classified as 'atypical' MPD. The oncogenic mutations(s) in classic MPD are unknown except for CML, which is associated with an activating mutation (Bcr/Abl) of the gene encoding for the Abl cytoplasmic protein kinase (PTK). In the last 3 months, a somatic point mutation of JAK2 (JAK2(V617F)), the gene encoding for another cytoplasmic PTK was reported in the majority of patients with PV and approximately half of those with either ET or MMM. The same mutation was also found in a small number of patients with either atypical MPD or the myelodysplastic syndrome but not in normal controls, germline tissue including T lymphocytes, and patients with secondary erythrocytosis. In vitro, JAK2(V617F) was associated with constitutive phosphorylation of JAK2 and its downstream effectors as well as induction of erythropoietin hypersensitivity in cell lines. In vivo, murine bone marrow transduced with a retrovirus containing JAK2(V617F) induced erythrocytosis in the transplanted mice. Taken together, these observations suggest that JAK2(V617F) is an acquired myeloid lineage-specific mutation that engenders a pathogenetic relevance for the PV phenotype in MPD.
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PMID:JAK2 in myeloproliferative disorders is not just another kinase. 1597 Jul 5

Essential thrombocythemia, polycythemia vera, and myelofibrosis with myeloid metaplasia constitute the "classic" bcr/abl-negative myeloproliferative disorders (MPDs). Each of these MPDs represents a stem cell-derived clonal myeloproliferation with the respective features of thrombocytosis, erythrocytosis, and bone marrow fibrosis. Unlike with cases of chronic myeloid leukemia, in which the bcr/abl mutation is invariably detected, current diagnosis of essential thrombocythemia, polycythemia vera, and myelofibrosis with myeloid metaplasia is based on a consensus-driven set of clinical and laboratory criteria that have undergone substantial modification in recent times. The recent discovery of a recurrent activating Janus tyrosine kinase (JAK2) mutation (JAK2VG17F) in all 3 classic MPDs offers another opportunity for refining current diagnoses and disease classifications. In this article, we outline contemporary diagnostic algorithms for each of these disorders and provide an evidence-based approach to management.
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PMID:bcr/abl-negative, classic myeloproliferative disorders: diagnosis and treatment. 1617 3

Polycythemia vera (PV) is a clonal disorder of unknown etiology involving a multipotent hematopoietic progenitor cell that is characterized by the accumulation of phenotypically normal red blood cells, white blood cells, and platelets in the absence of a definable cause; extramedullary hematopoiesis, marrow fibrosis, and, in a few patients, transformation to acute leukemia can also occur. First described in 1892, the cause of the disease remains unknown and no potentially curative therapy other than bone marrow transplantation is currently available. It is commonly held that PV is a rare disorder, when in fact with a minimum incidence of 2.6 per 100,000 it is more common than chronic myelogenous leukemia (CML) and is particularly prevalent in persons of Ashkenazi Jewish ancestry. However, the incidence of PV is not as high as that of erythrocytosis from other causes collectively, which poses a problem in differential diagnosis when PV presents as isolated erythrocytosis. Characteristic features of PV are erythropoietin (Epo)-independent in vitro erythroid colony formation, as well as hypersensitivity to many other hematopoietic growth factors. Recently, a remarkable association between PV and a somatic point mutation of the JAK2 tyrosine kinase (JAK2 V617F) was described. Functional assays have revealed that JAK2 V617F is capable of inducing constitutive STAT5-mediated signaling in vitro, as well as erythrocytosis in vivo in mice. These data suggest that the JAK2 V617F mutation participates in the pathogenesis of PV. In current clinical practice, two different clinical approaches have been used to diagnose PV. One approach requires establishing the presence of absolute erythrocytosis by directly determining the red cell mass (RCM). A second approach utilizes a RCM-independent diagnostic algorithm based on the serum Epo level and bone marrow histology. Screening for JAK2 V617F can now be added to both diagnostic algorithms. However, it is very clear that some patients with classical PV lack the JAK2 V617F mutation, while some patients with other chronic myeloproliferative disorders such as idiopathic myelofibrosis (IMF) and essential thrombocytosis (ET) also express the JAK2 V617F mutation. Therefore, by necessity, any discussion of PV must take into consideration these companion myeloproliferative disorders, and since erythrocytosis is the single clinical feature that sets PV apart from IMF and ET, it is clear that the presence of the JAK2 V617F mutation cannot by itself establish a diagnosis of PV. Phlebotomy remains the mainstay of therapy for PV. In addition, both aspirin and cytoreductive therapy have been employed to control thrombocytosis and in the case of the latter, leukocytosis and extramedullary hematopoiesis as well. Despite recent progress in the field, several important issues remain controversial. In this review, we will present the areas of agreement, but also point out where the authors' personal viewpoints differ.
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PMID:Polycythemia vera: scientific advances and current practice. 1621 34


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