Erythropoietin and the erythropoietin receptor

Dimerization or ligand-induced

Dimerization or ligand-induced

Jak2 Transphosphorylation
Figure 2.7 A summary of signalling via the Epo receptor as described in the text. P denotes regions of phosphorylation. The diagram shows Epo-induced dimerization or conformational change with transphosphorylation of JAK2, followed by

phosphorylation of the Epo receptor. This is followed by binding and phosphorylation of STAT5. Binding of SHP1 (far right) to the Epo receptor activates its phosphatase activity, which can then dephosphorylate JAK2 and terminate signalling.

Jak2 Transphosphorylation
Figure 2.8 A summary of the apoptotic pathways (Epo and Fas) in erythroid progenitors. These cells (BFU-E and CFU-E) undergo apoptosis in the absence of Epo signalling or in the presence of Fas signalling. Bcl-XL may be the key pathway through which these effects are mediated.

intracellular signalling pathways can support differentiation. Nevertheless, it is thought at present that these pathways may converge by activating a few, important anti-apoptotic proteins, including Bcl-2, Bcl-XL and protein kinase B (also known as Akt) (Figure 2.8).

The full control of this system is complex and it should be noted that the EpoR pathway can also be activated by other mechanisms. For example, activation of c-Kit by its ligand, stem cell factor (SCF), causes tyrosine phosphorylation of the EpoR and a functional interaction between the two receptors is essential for normal erythropoiesis.

Mechanisms for switching off the Epo-EpoR signalling pathway also exist. Specific phosphorylated tyrosines that occur on the Epo-stimulated dimerized EpoR provide docking sites for the SH2 domains of protein tyrosine phosphatases such as SHP1. Binding activates the phosphatase, which removes the activating phosphates from JAK2, terminating the positive signal from this pathway (Figure 2.7).

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