Erythropoietin receptor

The erythropoietin receptor (EpoR) is a 66 kDa peptide consisting of two peptide chains and is a member of the cytokine receptor family. Upon binding of a 34 kDa ligand erythropoietin (Epo), the two chains of the EpoR undergo a conformational change resulting in the autophosphorylation of Jak2 kinases that are pre-associated with the receptor (ie. EpoR does not possess intrinsic kinase activity and depends on Jak2 activity).

The cytoplasmic domains of the EpoR contain a number of phosphotyrosines that are phosphorylated by Jak2 and serve as docking sites for a variety of intracellular pathway activators and Stats (such as Stat5). In addition to activating Ras/MAP kinase, phosphatidylinositol 3-kinase/AKT pathway and STAT transcription factors, phosphotyrosines also serve as docking sites for phosphatases that negatively affect EpoR signaling to prevent overactivation that may lead to such disorders as erythrocytosis. Generally speaking, the defects in the erythropoietin receptor may produce erythroleukemia and familial erythrocytosis.

Interestingly, mice with truncated EpoR are viable, supporting the idea that Jak2 activity is sufficient to support basal erythropoiesis by activating the necessary pathways without phosphotyrosine docking sites being needed. EpoR-H form of EpoR truncation contains the first, and arguably the most important tyrosine 343 that serves as a docking site for the Stat5 molecule, but lacks the rest of the cytoplasmic tail. These mice exhibit elevated erythropoiesis consistent with the idea that phosphatase recruitment (and therefore the shutting down of signaling) is aberrant in these mice.

The EpoR-HM receptor lacks the cytoplasmic domain with the tyrosine 343 mutated to phenylalanine, making it unsuitable for efficient Stat5 docking and activation. These mice are anemic and show poor response to hypoxic stress, such as phenylhydrazine treatment or erythropoietin injection.

In erythroid progenitors, EpoR signaling is necessary to maintain progenitor survival as well as for the augmentation of the erythroid differentiation program that is largely dependent on transcriptional factor GATA-1 and others. It is important to realize, however, that by and large the pathways activated by EpoR are not unique to just the erythroid cells suggesting that the erythroid differentiation program, or any other lineage's program, does not just depend upon what receptor is expressed. It is also worth mentioning that other receptors on the surface of the erythroblast are also present.

Currently, a variety of groups have been working toward understanding which pathways does EpoR activate. Furthermore, important advances have been made in understanding how EpoR expression and Jak2/Stat activation in various cancers can be a contributing factor to tumorigenesis. Another important direction is how does EpoR signaling prevent neuronal death and ischemic injury.

^[1]

Interactions

Erythropoietin receptor has been shown to interact with STAT5A,^[2] SOCS3,^[3][4] PTPN6,^[5] LYN,^[6] Erythropoietin,^[7][8] Janus kinase 2,^[9][10] SOCS2,^[11] PIK3R1,^[12][13] Grb2^[14][15] and CRKL.^[16][17]

References

Further reading

v • d • e PDB Gallery 1cn4: ERYTHROPOIETIN COMPLEXED WITH EXTRACELLULAR DOMAINS OF ERYTHROPOIETIN RECEPTOR   1eba: COMPLEX BETWEEN THE EXTRACELLULAR DOMAIN OF ERYTHROPOIETIN (EPO) RECEPTOR [EBP] AND AN INACTIVE PEPTIDE [EMP33] CONTAINS 3,5-DIBROMOTYROSINE IN POSITION 4 (DENOTED DBY)   1ebp: COMPLEX BETWEEN THE EXTRACELLULAR DOMAIN OF ERYTHROPOIETIN (EPO) RECEPTOR [EBP] AND AN AGONIST PEPTIDE [EMP1]   1eer: CRYSTAL STRUCTURE OF HUMAN ERYTHROPOIETIN COMPLEXED TO ITS RECEPTOR AT 1.9 ANGSTROMS   1ern: NATIVE STRUCTURE OF THE EXTRACELLULAR DOMAIN OF ERYTHROPOIETIN (EPO) RECEPTOR [EBP]

External links

• MeSH Erythropoietin+Receptors

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