Back to Search
Start Over
Csk-binding protein controls red blood cell development via regulation of Lyn tyrosine kinase activity
- Source :
- Experimental hematology. 46
- Publication Year :
- 2016
-
Abstract
- Erythropoiesis is controlled principally through erythropoietin (Epo) receptor signaling, which involves Janus kinase 2 (JAK2) and Lyn tyrosine kinase, both of which are important for regulating red blood cell (RBC) development. Negative regulation of Lyn involves C-Src kinase (Csk)-mediated phosphorylation of its C-terminal tyrosine, which is facilitated by the transmembrane adaptor Csk-binding protein (Cbp). Although Cbp has significant functions in controlling Lyn levels and activity in erythroid cells in vitro, its importance to primary erythroid cell development and signaling has remained unclear. To address this, we assessed the consequence of loss of Cbp on the erythroid compartment in vivo and whether Epo-responsive cells isolated from Cbp-knockout mice exhibited altered signaling. Our data show that male Cbp−/− mice display a modest but significant alteration to late erythroid development in bone marrow with evidence of increased erythrocytes in the spleen, whereas female Cbp−/− mice exhibit a moderate elevation in early erythroid progenitors (not seen in male mice) that does not influence the later steps in RBC development. In isolated primary erythroid cells and cell lines generated from Cbp−/− mice, survival signaling through Lyn/Akt/FoxO3 was elevated, resulting in sustained viability during differentiation. The high Akt activity disrupted GAB2/SHP-2 feedback inhibition of Lyn; however, the elevated Lyn activity also increased inhibitory signaling via SHP-1 to restrict the Erk1/2 pathway. Interestingly, whereas loss of Cbp led to mild changes to late RBC development in male mice, this was not apparent in female Cbp−/− mice, possibly due to their elevated estrogen, which is known to facilitate early progenitor self-renewal.
- Subjects :
- 0301 basic medicine
Male
Cancer Research
Cell Survival
GAB2
Protein tyrosine phosphatase
environment and public health
Models, Biological
Cell Line
03 medical and health sciences
Mice
Erythroid Cells
LYN
hemic and lymphatic diseases
Genetics
Animals
Erythropoiesis
Molecular Biology
Protein kinase B
Mice, Knockout
Janus kinase 2
biology
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Forkhead Box Protein O3
Membrane Proteins
hemic and immune systems
Cell Differentiation
Cell Biology
Hematology
Phosphoproteins
Cell biology
Enzyme Activation
030104 developmental biology
src-Family Kinases
biology.protein
Cancer research
Female
Signal transduction
Tyrosine kinase
Proto-Oncogene Proteins c-akt
Protein Binding
Signal Transduction
Subjects
Details
- ISSN :
- 18732399
- Volume :
- 46
- Database :
- OpenAIRE
- Journal :
- Experimental hematology
- Accession number :
- edsair.doi.dedup.....1638a593ad3515236692568d40117c56