CELL-SURFACE ORGANIZATION OF THE ERYTHROPOIETIN RECEPTOR COMPLEX DIFFERS DEPENDING ON ITS MODE OF ACTIVATION

During erythroid development erythropoietin (EPO) binds specifically t o a receptor primarily present on committed erythroid progenitors, sti mulating mitogenic, survival, and differentiative growth response path ways, Other modes of erythropoietin receptor (EPO-R) activation, such as interaction with the env gene Friend virus envelope glycoprotein (F -gp55) of spleen focus-forming virus or specific mutations in the extr acellular domain of the EPO-R, give rise to pathological consequences, in vivo and EPO-independent proliferation and differentiation of cult ured cells, Activating extracellular receptor mutations result in cova lently linked receptor homodimers. These observations and others have led to the proposal that EPO activates the EPO-R by inducing dimer for mation on the cell surface. It has been assumed that F-gp55 also induc es dimer formation of the EPO-R; however, clear evidence of this is la cking, In addition, EPO and F-gp55 stimulation of the EPO-R elicit dif ferent biological responses. To probe whether the cell surface EPO-R i s structurally different with these activators, we contrasted the cell sw face EPO-R complex formed following receptor activation by EPO, F- gp55, and mutations in the extracellular domain of the receptor, Our r esults indicate that cell surface forms of activated EPO-R differ, as judged by their differential association with F-gp55 and pattern of as sociated cell surface proteins. Interestingly, we find that the env ge ne of an anemic strain of Friend virus, Rauscher virus envelope glycop rotein, does not interact with the EPO-R at the cell surface. Thus, th e mode of Rauscher virus envelope glycoprotein-induced erythroblastosi s may be distinct from F-gp55-induced erythroblastosis and possibly no t involve the EPO-R.