Disease relevance of Mpl

• Thrombocytopenia in c-mpl-deficient mice [1].
• Phage enzyme-linked immunosorbent assay was used to determine affinities for binding to both the TPO receptor and five anti-TPO1-153 monoclonal antibodies [2].
• Recently, we and others could define the molecular cause of the rare disease congenital amegakaryocytic thrombocytopenia (CAMT) as mutations in the c-mpl gene (Blood 97: 139, 2001) [3].
• Administration of 5-FU also produced thrombocytosis in previously splenectomized c-mpl(-/-) mice [4].
• The potential utility of c-mpl ligands for treatment of myelodysplastic syndromes, aplastic anemias, or in HIV infection, will have to be evaluated in the future [5].

High impact information on Mpl

• Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl [6].
• In mice, the c-mpl proto-oncogene is expressed in hematopoietic tissues as a 3 kb mRNA [7].
• Here we present evidence that the c-mpl-encoded receptor binds a ligand (c-Mpl ligand) which is a humoral factor implicated in platelet homeostasis [8].
• The isolated Mpl ligand shares homology with erythropoietin and stimulates both megakaryocytopoiesis and thrombopoiesis [9].
• These results along with those presented in the accompanying report strongly suggest that the ligand for c-Mpl is thrombopoietin [10].

Chemical compound and disease context of Mpl

• Circulating soluble MGDF receptor levels (c-mpl) do not change significantly during the course of carboplatin-induced thrombocytopenia [11].

Biological context of Mpl

• In this report, eight carboxyl truncations of the 121-aa murine Mpl cytoplasmic domain were tested for the ability to support growth of a cytokine-dependent cell line (Ba/F3) and for their capacity to induce TPO-stimulated tyrosine phosphorylation of specific signaling proteins [12].
• Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-Mpl [13].
• Furthermore, TPO-stimulated cellular proliferation appears to be directly correlated with receptor internalization, indicating that internalization of the TPO/Mpl complex may be essential for normal signal transduction [14].
• These data help identify the receptor motifs involved in TPO-induced internalization of Mpl and suggest that Mpl translocation may be necessary for normal cellular proliferation [14].
• Since the anti-FLAG antibodies do not react with the TPO binding site of the receptor, we hypothesize that they can trigger a distinct signal by dimerizing Mpl in a manner different from that induced by TPO [15].

Anatomical context of Mpl

• Thrombopoietin (TPO) acts through its receptor, Mpl, to stimulate the proliferation and maturation of megakaryocytes and their progenitors [12].
• Forced GATA-1 expression in the murine myeloid cell line M1: induction of c-Mpl expression and megakaryocytic/erythroid differentiation [16].
• We examined whole embryos or the cells isolated from embryo proper and yolk sacs and identified both Tpo and c-mpl (Tpo receptor) mRNA transcripts in tissues as early as embryonic day 6.5 (E6.5) [17].
• However, little is known about the effects of TPO on nonhematopoietic cells expressing the TPO receptor, such as endothelial cells (EC) [18].
• Hematopoietic stem cell deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin [19].

Associations of Mpl with chemical compounds

• A structure-function analysis of serine/threonine phosphorylation of the thrombopoietin receptor, c-Mpl [20].
• MATERIALS AND METHODS: Delta60-Mpl knockin mice, Stat5a(-/-)/b(-/-), Stat5a(-/-), and Stat5b(-/-) mice and wild-type (WT) controls were given a lethal myelosuppressive regimen: 80 mg/kg carboplatin intravenously followed by 7.5 or 6.5 Gy 137Cs total-body irradiation [21].
• The SH2 domains of CIS1, constructed as glutathione S-transferase fusion protein, bound to activated Mpl in vitro [22].
• Comparison of the platelet response to 5-FU in young (6-12 weeks) and old (33-46 weeks) c-mpl(-/-) mice found that older mice produced a much more marked response than younger mice, with a mean maximum platelet level of approximately 1700 x 10(9)/L [4].
• Enforced expression of c-mpl in embryonic stem (ES) cells inactivated for this gene results in protein expression in all the ES cell progeny, producing cells that do not belong to the megakaryocytic lineage and are responsive to PEG-rhuMGDF, a truncated form of human thrombopoietin (TPO) conjugated to polyethylene glycol [23].

Physical interactions of Mpl

• OBJECTIVE: Blood levels of thrombopoietin (TPO) are regulated in part by cellular degradation following its binding to the cell surface receptor c-mpl [24].

Regulatory relationships of Mpl

• MATERIALS AND METHODS: A cassette coding for MplK cDNA was introduced into parental and MplP-expressing BaF3 cells and TPO-mediated cell growth studied [25].
• OBJECTIVE: To determine the role of the c-terminal half of c-Mpl in Mpl-L-induced myeloprotection and the importance of Stat5 isoforms in the survival signaling pathways induced by Mpl ligand [21].
• We have previously demonstrated that cyclin D3 is expressed in megakaryocytes and is induced upon treatment with Mpl ligand [26].
• In response to literature reports of Mpl ligand-induced transient increases in p21Cip1/WAF1 mRNA in polyploidizing megakaryocytic cell lines, we have examined p21 transcript levels in both normal and transgenic megakaryocytes [26].
• The Mpl-type SAGs induced more potent proliferation of Ba/F3 and cynomolgus CD34(+) cells than the GCR-type SAG [27].

Other interactions of Mpl

• Thrombopoietin (TPO), the ligand for the receptor protooncogene c-mpl, has been cloned and shown to be the critical regulator of platelet production [28].
• The activity of the c-mpl promoter in the presence of cotransfected GATA-1 was significantly increased compared with that of the control [16].
• Cytokine production and function in c-mpl-deficient mice: no physiologic role for interleukin-3 in residual megakaryocyte and platelet production [29].
• Functional regions of the mouse thrombopoietin receptor cytoplasmic domain: evidence for a critical region which is involved in differentiation and can be complemented by erythropoietin [30].
• Furthermore, previous studies of the physical interaction between Mpl and the JAKs are extended, showing a difference in the association of JAK2 and TYK2 with the TPO receptor [31].

Analytical, diagnostic and therapeutic context of Mpl

• Similarly, Western blot analysis of MKs produced in the presence or absence of TPO showed no difference in Mpl levels [32].
• Thrombopoietin and the c-Mpl receptor: insights from gene targeting [33].
• Genomic sequence analysis identified differential splicing of alternative exon 4 sequences as the likely basis for these transcripts, which are predicted to encode receptors which differ within the first Mpl hematopoietin receptor domain [34].
• Engineering of cell lines expressing c-mpl provided a sensitive tool for detecting the ligand of Mpl, and led to the molecular cloning of TPO, the long sought proliferation and differentiation factor for the megakaryocytic lineage [35].
• In serial transplantation experiments, STAT5ab(-/-) and c-Mpl(-/-) BM both failed to provide consistent engraftment in tertiary hosts and could not radioprotect lethally irradiated quaternary recipients [36].

References