We have cloned the human homolog of the v-mpl oncogene transduced in the myeloproliferative leukemia retrovirus, which presents striking homologies with members of the hematopoietin receptor superfamily. We obtained two types of clones, MPLP and MPLK, which had the same 5' extremity but differed at their 3' ends. The resulting deduced polypeptides are composed of a common extracellular domain with a putative signal sequence and a common transmembrane domain, but they differ in their cytoplasmic domain after a stretch of 9 common amino acids. The extracellular domain of MPL contains the consensus sequences described for the members of the hematopoietin receptor superfamily. In addition, as for murine interleukin 3 and human and murine granulocytemacrophage colony-stimulating factor type (3 receptors, this domain can be divided into two subunits. An additional motif specific for MPL could be displayed by hydrophobic cluster analysis in the first subdomain. When RNAs from various hematopoietic cell lines were analyzed by Northern blot, MPL was detected only in the human erythroleukemia (HEL) cell line as a major 3.7-kilobase (kb) mRNA (MPLP) and a minor 2.8-kb mRNA (MPLK). However, study of MPL expression by PCR analysis indicated that MPL is expressed at a low level in a large number of cells of hematopoietic origin and that the two types of mRNAs (P and K) were always found to be coexpressed.The myeloproliferative leukemia virus (MPLV) is an acute leukemogenic murine retrovirus that displays unique biological features since, upon in vivo infection, a broad spectrum of MPLV-infected hematopoietic progenitors immediately acquired factor independence for both proliferation and terminal differentiation (1, 2). Moreover, direct in vitro infection ofbone marrow cells gave rise to a variety of autonomous cell lines that probably derived from the outgrowth of infected multipotential stem cells (3).In a previous report (3), we showed that MPLV has transduced in its envelope a cellular oncogene named v-mpl that shares striking structural similarities with members of the cytokine receptor superfamily.The extracellular domains of these growth factor receptors are organized in 200 amino acid modules that display a distinctive conservation of four cysteine residues at their N terminus and a WSXWS box close to the transmembrane domain (4). No consensus sequence for kinase activity can be detected in the cytoplasmic region (5).In the present paper, we describe the molecular cloning of the human MPL protooncogene. 1 1 Two families of human cDNA clones were obtained, which share common extracellular and transmembrane domains but differ in their cytoplasmic regions. Sequence analysis indicated that human MPL shares overall structural and amino acid homology with members of the cytokine receptor superfamily. Like the murine interleukin 3 (IL-3) receptor (6), the extracellular region of MPL can be divided into two subunits. No consensus sequence for tyrosine kinase activity could be detected in the cytoplasmic domain of eithe...
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