CHARACTERIZATION OF THE MURINE MPL PROTOONCOGENE, A MEMBER OF THE HEMATOPOIETIC CYTOKINE RECEPTOR FAMILY - MOLECULAR-CLONING, CHROMOSOMAL LOCATION AND EVIDENCE FOR A FUNCTION IN CELL-GROWTH

The v-mpl oncogene transduced in the myeloproliferative leukemia virus (MPLV) encodes a truncated form of a putative receptor protein that b elongs to the cytokine receptor superfamily. We previously reported th e cloning of complete human c-MPL cDNA. In the present report, we show that the murine Mpl proto-oncogene is located at the D-band of murine chromosome 4, in a region in synteny with human chromosome 1p34, wher e MPL was previously located. RNA blot analysis of murine hematopoieti c tissues and cells lines indicated that Mpl is expressed in immature hematopoietic precursor cells. Molecular cloning of murine proto-oncog ene c-Mpl cDNAs is also reported. Two cDNA species were isolated. One potentially encodes a transmembrane protein. The extracellular domain of this protein has two repeats of the cytokine receptor domain common to all members of this receptor family. The cytoplasmic domain has no protein kinase or phosphatase motifs, but does contain a sequence tha t has been shown to be essential for the transmission of a growth sign al in several other members of the family. Comparison of murine and hu man putative proteins indicated that they shared 81% amino acid identi ty, the most conserved region being the cytoplasmic domain (91% identi ty). The other Mpl cDNA clones potentially encode a soluble form of th is receptor chain. A chimeric receptor containing the extracellular do main of the granulocyte colony-stimulating factor (G-CSF) receptor fus ed to the transmembrane and cytoplasmic domains of Mpl was able to ind uce G-CSF responsiveness when transfected into the interleukin 3 (IL-3 )-dependent cell line BAF/BO3. This demonstrated that the cytoplasmic Mpl domain is most probably implicated in proliferative signal transdu ction.