The Distal Region and Receptor Tyrosines of the Epo Receptor Are Non-essential for in Vivo Erythropoiesis

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2001 Jun 19

PMID 11406592

Citations 43

Authors

H Zang

K Sato

H Nakajima

C Mckay

P A Ney

J N Ihle

Affiliations

Soon will be listed here.

Abstract

The erythropoietin receptor (EpoR) is required for the proliferation and survival of committed erythroid lineage cells. Previous studies have utilized receptor mutations to show the requirement for the distal half of the cytoplasmic domain of the EpoR and receptor tyrosines for activation of signaling pathways potentially critical to Epo function. To extend these studies to in vivo erythropoiesis, we have created two mutant strains of mice. One strain (H) contains a truncation of the distal half of the cytoplasmic domain, while the second strain (HM) contains the same truncation as well as the mutation of the residual tyrosine (Y(343)) to a phenylalanine. Strikingly, both strains of mice are viable, with only slight alterations in constitutive erythropoiesis or in in vitro assays of red cell lineage function. Challenging H mutant mice with continuous injections of Epo results in an erythrocytosis that is not seen in HM mice. The results demonstrate that neither the distal region nor receptor tyrosines are essential for in vivo EpoR function, but contribute to receptor function in a subtle manner.

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References

Divoky V, Liu Z, Ryan T, Prchal J, Townes T, Prchal J . Mouse model of congenital polycythemia: Homologous replacement of murine gene by mutant human erythropoietin receptor gene. Proc Natl Acad Sci U S A. 2001; 98(3):986-91. PMC: 14696. DOI: 10.1073/pnas.98.3.986. View

Marine J, Mckay C, Wang D, Topham D, Parganas E, Nakajima H . SOCS3 is essential in the regulation of fetal liver erythropoiesis. Cell. 1999; 98(5):617-27. DOI: 10.1016/s0092-8674(00)80049-5. View

Krantz S . Erythropoietin. Blood. 1991; 77(3):419-34. View

DAndrea A, Yoshimura A, Youssoufian H, Zon L, Koo J, Lodish H . The cytoplasmic region of the erythropoietin receptor contains nonoverlapping positive and negative growth-regulatory domains. Mol Cell Biol. 1991; 11(4):1980-7. PMC: 359883. DOI: 10.1128/mcb.11.4.1980-1987.1991. View

de la Chapelle A, Traskelin A, Juvonen E . Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis. Proc Natl Acad Sci U S A. 1993; 90(10):4495-9. PMC: 46538. DOI: 10.1073/pnas.90.10.4495. View

Shultz L, Schweitzer P, Rajan T, Yi T, Ihle J, Matthews R . Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell. 1993; 73(7):1445-54. DOI: 10.1016/0092-8674(93)90369-2. View

Witthuhn B, Quelle F, Silvennoinen O, Yi T, Tang B, Miura O . JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell. 1993; 74(2):227-36. DOI: 10.1016/0092-8674(93)90414-l. View

van Deursen J, Heerschap A, Oerlemans F, Ruitenbeek W, Jap P, Ter Laak H . Skeletal muscles of mice deficient in muscle creatine kinase lack burst activity. Cell. 1993; 74(4):621-31. DOI: 10.1016/0092-8674(93)90510-w. View

Sawai S, Shimono A, Wakamatsu Y, Palmes C, Hanaoka K, Kondoh H . Defects of embryonic organogenesis resulting from targeted disruption of the N-myc gene in the mouse. Development. 1993; 117(4):1445-55. DOI: 10.1242/dev.117.4.1445. View

10.

Moens C, Stanton B, Parada L, Rossant J . Defects in heart and lung development in compound heterozygotes for two different targeted mutations at the N-myc locus. Development. 1993; 119(2):485-99. DOI: 10.1242/dev.119.2.485. View

11.

Yi T, Zhang J, Miura O, Ihle J . Hematopoietic cell phosphatase associates with erythropoietin (Epo) receptor after Epo-induced receptor tyrosine phosphorylation: identification of potential binding sites. Blood. 1995; 85(1):87-95. View

12.

Motoyama N, Wang F, Roth K, Sawa H, Nakayama K, Negishi I . Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science. 1995; 267(5203):1506-10. DOI: 10.1126/science.7878471. View

13.

Klingmuller U, Lorenz U, Cantley L, Neel B, Lodish H . Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell. 1995; 80(5):729-38. DOI: 10.1016/0092-8674(95)90351-8. View

14.

Sokol L, Luhovy M, Guan Y, Prchal J, Semenza G, Prchal J . Primary familial polycythemia: a frameshift mutation in the erythropoietin receptor gene and increased sensitivity of erythroid progenitors to erythropoietin. Blood. 1995; 86(1):15-22. View

15.

Wu H, Liu X, Jaenisch R, Lodish H . Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell. 1995; 83(1):59-67. DOI: 10.1016/0092-8674(95)90234-1. View

16.

Damen J, CUTLER R, Jiao H, Yi T, Krystal G . Phosphorylation of tyrosine 503 in the erythropoietin receptor (EpR) is essential for binding the P85 subunit of phosphatidylinositol (PI) 3-kinase and for EpR-associated PI 3-kinase activity. J Biol Chem. 1995; 270(40):23402-8. DOI: 10.1074/jbc.270.40.23402. View

17.

Adachi M, Suematsu S, Kondo T, Ogasawara J, Tanaka T, Yoshida N . Targeted mutation in the Fas gene causes hyperplasia in peripheral lymphoid organs and liver. Nat Genet. 1995; 11(3):294-300. DOI: 10.1038/ng1195-294. View

18.

Damen J, Wakao H, Miyajima A, Krosl J, Humphries R, CUTLER R . Tyrosine 343 in the erythropoietin receptor positively regulates erythropoietin-induced cell proliferation and Stat5 activation. EMBO J. 1995; 14(22):5557-68. PMC: 394670. DOI: 10.1002/j.1460-2075.1995.tb00243.x. View

19.

Tauchi T, Damen J, Toyama K, Feng G, Broxmeyer H, Krystal G . Tyrosine 425 within the activated erythropoietin receptor binds Syp, reduces the erythropoietin required for Syp tyrosine phosphorylation, and promotes mitogenesis. Blood. 1996; 87(11):4495-501. View

20.

Gobert S, Chretien S, Gouilleux F, Muller O, Pallard C, Dusanter-Fourt I . Identification of tyrosine residues within the intracellular domain of the erythropoietin receptor crucial for STAT5 activation. EMBO J. 1996; 15(10):2434-41. PMC: 450175. View