Nature 348, 647 - 649 (13 December 1990); doi:10.1038/348647a0

Point mutation in the exoplasmic domain of the erythropoietin receptor resulting in hormone-independent activation and tumorigenicity

Akihiko Yoshimura^*, Gregory Longmore^*† & Harvey F. Lodish^*‡

^*Whitehead Institute for Biomedical Research, Nine Cambridge Center,Cambridge, Massachusetts 02142, USA
^†Division of Hematology and Medicine, Brigham and Women's Hospital,Harvard Medical School, Boston, Massachusetts 02115 and
^‡Department of Biology, Massachusetts Institute of Technology,Cambridge, Massachusetts 02138, USA

THE receptors for erythropoietin and other cytokines constitute a new superfamily^1–4. They have no tyrosine-kinase or other enzyme motif and their signal-transducing mechanism is unclear. Here we describe two classes of activating mutations in the erythropoietin receptor (EPOR). A single point mutation in the exoplasmic domain enables it to induce hormone-independent cell growth and tumorigenesis after expression in nontumorigenic, interleukin-3-dependent haematopoietic cells. A C-terminal truncation in the cytoplasmic domain of the EPOR renders the receptor hyper-responsive to erythropoietin, but is insufficient to induce hormone-independent growth or tumorigenicity. The activating point mutation retards intracellular transport and turnover of the receptor. These alterations in metabolism and tumorigenicity caused by the EPOR with activating point mutations are similar to those observed in erythropoietin-independent activation of the wild type EPOR by association with gp55, the Friend spleen focus-forming virus glycoprotein^5,6.

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