Inactivation of Erythropoietin Receptor Function by Point Mutations in a Region Having Homology with Other Cytokine Receptors

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 1993 Mar 1

PMID 8382775

Citations 45

Authors

O Miura

J L Cleveland

J N Ihle

Affiliations

Soon will be listed here.

Abstract

The cytoplasmic domain of the erythropoietin receptor (EpoR) contains a region, proximal to the transmembrane domain, that is essential for function and has homology with other members of the cytokine receptor family. To explore the functional significance of this region and to identify critical residues, we introduced several amino acid substitutions and examined their effects on erythropoietin-induced mitogenesis, tyrosine phosphorylation, and expression of immediate-early (c-fos, c-myc, and egr-1) and early (ornithine decarboxylase and T-cell receptor gamma) genes in interleukin-3-dependent cell lines. Amino acid substitution of W-282, which is strictly conserved at the middle portion of the homology region, completely abolished all the functions of the EpoR. Point mutation at L-306 or E-307, both of which are in a conserved LEVL motif, drastically impaired the function of the receptor in all assays. Other point mutations, introduced into less conserved amino acid residues, did not significantly impair the function of the receptor. These results demonstrate that conserved amino acid residues in this domain of the EpoR are required for mitogenesis, stimulation of tyrosine phosphorylation, and induction of immediate-early and early genes.

Citing Articles

Targeting low-risk myelodysplastic syndrome with novel therapeutic strategies.

Trivedi G, Inoue D, Zhang L Trends Mol Med. 2021; 27(10):990-999.

PMID: 34257007 PMC: 8487963. DOI: 10.1016/j.molmed.2021.06.013.

Cytokine receptor splice variants in hematologic diseases.

Wang B, Mehta H Cytokine. 2019; 127:154919.

PMID: 31816579 PMC: 6995764. DOI: 10.1016/j.cyto.2019.154919.

Inhibition of the STAT5/Pim Kinase Axis Enhances Cytotoxic Effects of Proteasome Inhibitors on FLT3-ITD-Positive AML Cells by Cooperatively Inhibiting the mTORC1/4EBP1/S6K/Mcl-1 Pathway.

Nogami A, Okada K, Ishida S, Akiyama H, Umezawa Y, Miura O Transl Oncol. 2018; 12(2):336-349.

PMID: 30472492 PMC: 6335494. DOI: 10.1016/j.tranon.2018.11.001.

Mechanisms for mTORC1 activation and synergistic induction of apoptosis by ruxolitinib and BH3 mimetics or autophagy inhibitors in JAK2-V617F-expressing leukemic cells including newly established PVTL-2.

Ishida S, Akiyama H, Umezawa Y, Okada K, Nogami A, Oshikawa G Oncotarget. 2018; 9(42):26834-26851.

PMID: 29928488 PMC: 6003557. DOI: 10.18632/oncotarget.25515.

FLT3-ITD induces expression of Pim kinases through STAT5 to confer resistance to the PI3K/Akt pathway inhibitors on leukemic cells by enhancing the mTORC1/Mcl-1 pathway.

Okada K, Nogami A, Ishida S, Akiyama H, Chen C, Umezawa Y Oncotarget. 2018; 9(10):8870-8886.

PMID: 29507660 PMC: 5823622. DOI: 10.18632/oncotarget.22926.

References

Conscience J, Verrier B, Martin G . Interleukin-3-dependent expression of the c-myc and c-fos proto-oncogenes in hemopoietic cell lines. EMBO J. 1986; 5(2):317-23. PMC: 1166735. DOI: 10.1002/j.1460-2075.1986.tb04215.x. View

PIERCE J, Di Fiore P, Aaronson S, Potter M, Pumphrey J, Scott A . Neoplastic transformation of mast cells by Abelson-MuLV: abrogation of IL-3 dependence by a nonautocrine mechanism. Cell. 1985; 41(3):685-93. DOI: 10.1016/s0092-8674(85)80049-0. View

Clark S, Kamen R . The human hematopoietic colony-stimulating factors. Science. 1987; 236(4806):1229-37. DOI: 10.1126/science.3296190. View

Dean M, Cleveland J, Rapp U, Ihle J . Role of myc in the abrogation of IL3 dependence of myeloid FDC-P1 cells. Oncogene Res. 1987; 1(3):279-96. View

Kipreos E, Wang J . Reversible dependence on growth factor interleukin-3 in myeloid cells expressing temperature sensitive v-abl oncogene. Oncogene Res. 1988; 2(3):277-84. View

DAndrea A, Lodish H, Wong G . Expression cloning of the murine erythropoietin receptor. Cell. 1989; 57(2):277-85. DOI: 10.1016/0092-8674(89)90965-3. View

Metcalf D . The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells. Nature. 1989; 339(6219):27-30. DOI: 10.1038/339027a0. View

Weinstein Y, Morishita K, Cleveland J, Ihle J . Interleukin 3 (IL-3) induces transcription from nonrearranged T cell receptor gamma loci in IL-3-dependent cell lines. J Exp Med. 1989; 169(6):2059-71. PMC: 2189342. DOI: 10.1084/jem.169.6.2059. View

Migliaccio G, Migliaccio A, Kreider B, Rovera G, Adamson J . Selection of lineage-restricted cell lines immortalized at different stages of hematopoietic differentiation from the murine cell line 32D. J Cell Biol. 1989; 109(2):833-41. PMC: 2115740. DOI: 10.1083/jcb.109.2.833. View

10.

Bazan J . A novel family of growth factor receptors: a common binding domain in the growth hormone, prolactin, erythropoietin and IL-6 receptors, and the p75 IL-2 receptor beta-chain. Biochem Biophys Res Commun. 1989; 164(2):788-95. DOI: 10.1016/0006-291x(89)91528-3. View

11.

Cleveland J, Dean M, Rosenberg N, Wang J, Rapp U . Tyrosine kinase oncogenes abrogate interleukin-3 dependence of murine myeloid cells through signaling pathways involving c-myc: conditional regulation of c-myc transcription by temperature-sensitive v-abl. Mol Cell Biol. 1989; 9(12):5685-95. PMC: 363740. DOI: 10.1128/mcb.9.12.5685-5695.1989. View

12.

Hatakeyama M, Mori H, Doi T, Taniguchi T . A restricted cytoplasmic region of IL-2 receptor beta chain is essential for growth signal transduction but not for ligand binding and internalization. Cell. 1989; 59(5):837-45. DOI: 10.1016/0092-8674(89)90607-7. View

13.

Kono T, Doi T, Yamada G, Hatakeyama M, Minamoto S, Tsudo M . Murine interleukin 2 receptor beta chain: dysregulated gene expression in lymphoma line EL-4 caused by a promoter insertion. Proc Natl Acad Sci U S A. 1990; 87(5):1806-10. PMC: 53572. DOI: 10.1073/pnas.87.5.1806. View

14.

Ullrich A, Schlessinger J . Signal transduction by receptors with tyrosine kinase activity. Cell. 1990; 61(2):203-12. DOI: 10.1016/0092-8674(90)90801-k. View

15.

Yoshimura A, DAndrea A, Lodish H . Friend spleen focus-forming virus glycoprotein gp55 interacts with the erythropoietin receptor in the endoplasmic reticulum and affects receptor metabolism. Proc Natl Acad Sci U S A. 1990; 87(11):4139-43. PMC: 54063. DOI: 10.1073/pnas.87.11.4139. View

16.

Roussel M, Shurtleff S, Downing J, Sherr C . A point mutation at tyrosine-809 in the human colony-stimulating factor 1 receptor impairs mitogenesis without abrogating tyrosine kinase activity, association with phosphatidylinositol 3-kinase, or induction of c-fos and junB genes. Proc Natl Acad Sci U S A. 1990; 87(17):6738-42. PMC: 54612. DOI: 10.1073/pnas.87.17.6738. View

17.

Quelle F, Wojchowski D . Proliferative action of erythropoietin is associated with rapid protein tyrosine phosphorylation in responsive B6SUt.EP cells. J Biol Chem. 1991; 266(1):609-14. View

18.

Horak I, Gress R, Lucas P, Horak E, Waldmann T, Bolen J . T-lymphocyte interleukin 2-dependent tyrosine protein kinase signal transduction involves the activation of p56lck. Proc Natl Acad Sci U S A. 1991; 88(5):1996-2000. PMC: 51153. DOI: 10.1073/pnas.88.5.1996. View

19.

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

20.

Koch C, Anderson D, Moran M, Ellis C, Pawson T . SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins. Science. 1991; 252(5006):668-74. DOI: 10.1126/science.1708916. View