Integrative signaling by minimal erythropoietin receptor forms and c-kit

Erythroid homeostasis depends critically upon erythropoietin (Epo) and stem cell factor cosignaling in late progenitor cells. Epo bioresponses are rel ayed efficiently by minimal receptor forms that retain a single Tyr-343 sit e for STATE binding, while forms that lack all cytoplasmic Tyr(P) sites act ivate JAK2 and the transcription of c-Myc plus presumed additional target g enes. In FDCER cell lines, which express endogenous c-Kit, the signaling ca pacities of such minimal Epo receptor forms (ER-HY343 and ER-HY343F) have b een dissected to reveal: 1) that Epo-dependent mitogenesis, survival, and b cl-x gene expression via ER-HY343 depend upon the intactness of the Tyr-343 STATE binding site; 2) that ER-HY343-dependent bcl-x(L) gene transcription is enhanced markedly via c-Kit; 3) that socs-3, plfap, dpp-l, and cacy-bp gene transcription is induced via ER-HY343, whereas dpp-1 and cacy-bp gene expression is also supported by ER-HY343F; 4) that ectopically expressed SO CS-3 suppresses proliferative signaling by not only ER-HY343 but also c-Kit ; and 5) that in FDCER and primary erythroid cells, c-Kit appears to provid e the primary route to MAPK activation. Thus, integration circuits exist in only select downstream pathways within Epo and stem call factor receptor s ignaling.