Murine c-mpl: a member of the hematopoietic growth factor receptor superfamily that transduces a proliferative signal.

Abstract

The murine myeloproliferative leukemia virus has previously been shown to contain a fragment of the coding region of the c‐mpl gene, a member of the cytokine receptor superfamily. We have isolated cDNA and genomic clones encoding murine c‐mpl and localized the c‐mpl gene to mouse chromosome 4. Since some members of this superfamily function by transducing a proliferative signal and since the putative ligand of mpl is unknown, we have generated a chimeric receptor to test the functional potential of mpl. The chimera consists of the extracellular domain of the human interleukin‐4 receptor and the cytoplasmic domain of mpl. A mouse hematopoietic cell line transfected with this construct proliferates in response to human interleukin‐4, thereby demonstrating that the cytoplasmic domain of mpl contains all elements necessary to transmit a growth stimulatory signal. In addition, we show that 25–40% of mpl mRNA found in the spleen corresponds to a novel truncated and potentially soluble isoform of mpl and that both full‐length and truncated forms of mpl protein can be immunoprecipitated from lysates of transfected COS cells. Interestingly, however, although the truncated form of the receptor possesses a functional signal sequence and lacks a transmembrane domain, it is not detected in the culture media of transfected cells.

The molecular and cellular biology of thrombopoietin: the primary regulator of platelet production

“…This protein has no known biological activity, has not been shown to transduce a proliferative signal, and could potentially act as a dominant negative receptor by heterodimerizing with Mpl-P after ligand binding. The third mRNA species, found in both human and murine cells, encodes a potentially secreted form of Mpl due to alternative splicing of exon 8 directly to exon 11, eliminating the juxtamembrane WSXWS motif, the transmembrane domain, and the initial cytoplasmic residues (Vigon et al, 1992;Skoda et al, 1993;Mignotte et al, 1994). It is not known whether this protein is actually secreted by hematopoietic cells nor whether it is able to bind TPO.…”

“…Since that time the proto-oncogene c-mpl was identi®ed and, based on homology arguments, believed to encode a hematopoietic cytokine receptor, a hypothesis later proven when the cytoplasmic domain was linked to the ligand binding domain of the IL-4 receptor and shown to support the IL-4 induced growth of hematopoietic cells (Skoda et al, 1993). Finally, two di erent strategies using c-mpl lead to the identi®cation of a novel ligand for the receptor in 1994 (de Sauvage et al, 1994;Lok et al, 1994;Bartley et al, 1994), a protein that displays all the biologic properties of TPO.…”

A Truncated Isoform of c-Mpl with an Essential C-terminal Peptide Targets the Full-length Receptor for Degradation

“…The second mRNA variant encodes a truncated soluble receptor, Mpl-tr, and is the only one found both in human and mouse. This variant results from splicing of exon 8 directly to exon 11, eliminating the juxtamembrane extracellular part and the transmembrane domain (12,13). Due to an altered reading frame at the splice acceptor site of exon 11, Mpl-tr protein terminates in a short stretch of novel amino acid sequences (see Fig.…”

“…mpl-tr mRNA accounts for ϳ30% of mpl mRNA in mouse spleen (12). Despite the presence of a signal sequence and the lack of a transmembrane domain, Mpl-tr is not secreted into the cell supernatant when ectopically expressed in cell line (12). In humans, two alternate mRNA mpl species are known in addition to mpl-tr.…”

Identification of Functional Domains of the Human Thrombopoietin Receptor Required for Growth and Differentiation of Megakaryocytic Cells

“…The c-mpl protooncogene was first identified as the cellular homolog of the viral oncogene v-mpl in the myeloproliferative leukemia virus (6). Based on homology with a member of the cytokine receptor superfamily, however, the c-mpl gene was predicted to encode a cytokine receptor (7)(8)(9). Experiments with an antisense oligomer against c-mpl and c-mpl-deficient mice revealed that the c-mpl gene encodes the receptor for TPO.…”