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 relayed efficiently by minimal receptor forms that retain a single Tyr-343 site for STAT5 binding, while forms that lack all cytoplasmic Tyr(P) sites activate JAK2 and the transcription of c-Myc plus presumed additional target genes. In FDCER cell lines, which express endogenous c-Kit, the signaling capacities of such minimal Epo receptor forms (ER-HY343 and ER-HY343F) have been dissected to reveal: 1) that Epo-dependent mitogenesis, survival, and bcl-x gene expression via ER-HY343 depend upon the intactness of the Tyr-343 STAT5 binding site; 2) that ER-HY343-dependent bcl-x(L) gene transcription is enhanced markedly via c-Kit; 3) that socs-3, plfap, dpp-1, 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 SOCS-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 provide the primary route to MAPK activation. Thus, integration circuits exist in only select downstream pathways within Epo and stem call factor receptor signaling.
Pircher
T J
TJ
Department of Veterinary Science, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Geiger
J N
JN
Zhang
D
D
Miller
C P
CP
Gaines
P
P
Wojchowski
D M
DM
D001483:Base Sequence; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D017931:DNA Primers; D004789:Enzyme Activation; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D017467:Receptors, Erythropoietin / Q000378:metabolism*; D015398:Signal Transduction
D017931:DNA Primers; D017467:Receptors, Erythropoietin; D019009:Proto-Oncogene Proteins c-kit; D020928:Mitogen-Activated Protein Kinases