title: Erythropoietin-dependent inhibition of apoptosis is supported by carboxyl-truncated receptor forms and blocked by dominant-negative forms of Jak2.
abstract: Apoptosis, or programmed cell death (PCD), recently has emerged as an important homeostatic mechanism within several hematopoietic lineages. This process is subject to both positive and negative modulation by cytokines and within the erythroid lineage is inhibited by interleukin-3, stem cell factor, and erythropoietin (Epo). Through the expression of carboxyl-truncated Epo receptor mutants in FDC-P1 cells, a receptor form possessing 80 membrane-proximal cytoplasmic residues is shown to efficiently mediate Epo-dependent inhibition of PCD. This is in contrast to previous studies that attributed this activity to a distal carboxyl-terminal receptor subdomain (and/or heterodimerization of wild type Epo receptors with a truncated non-functional receptor form). Epo-dependent inhibition of PCD also is shown to be blocked by ectopic expression of kinase-deficient dominant-negative forms of Jak2 (Jak2 delta VIII and Jak2-829), further underlining a role of this membrane-proximal subdomain of the Epo receptor in the inhibition of PCD. To our knowledge, this comprises the first direct evidence for an essential role for a Jak tyrosine kinase (Jak2) in this apoptotic response pathway.
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park 16802, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhuang
authors.forename: Z
authors.initials: Z
authors.lastname: Niu
authors.forename: T C
authors.initials: TC
authors.lastname: He
authors.forename: S V
authors.initials: SV
authors.lastname: Patel
authors.forename: D M
authors.initials: DM
authors.lastname: Wojchowski
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D004921:Erythropoietin / Q000494:pharmacology*; D053614:Janus Kinase 2; D051379:Mice; D008969:Molecular Sequence Data; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins
chemical_list: D011518:Proto-Oncogene Proteins; D004921:Erythropoietin; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2