The SH2B1 adaptor protein associates with a proximal region of the erythropoietin receptor.

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  • Additional Information
    • Source:
      Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
    • Publication Information:
      Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
      Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
    • Subject Terms:
      Adaptor Proteins, Signal Transducing/*metabolism ; Receptors, Erythropoietin/*metabolism; Adaptor Proteins, Signal Transducing/chemistry ; Adaptor Proteins, Signal Transducing/isolation & purification ; Animals ; Cell Line ; Erythroblasts/metabolism ; Erythropoietin/physiology ; Humans ; Immunoprecipitation ; Mice ; Mice, Inbred C57BL ; Peptide Fragments/chemistry ; Peptide Fragments/isolation & purification ; Peptide Fragments/metabolism ; Phosphorylation ; Primary Cell Culture ; Protein Interaction Domains and Motifs ; Protein Processing, Post-Translational ; Receptors, Erythropoietin/chemistry ; Receptors, Erythropoietin/isolation & purification ; Signal Transduction
    • Abstract:
      Gene targeting experiments have shown that the cytokine erythropoietin (EPO), its cognate erythropoietin receptor (EPO-R), and associated Janus tyrosine kinase, JAK2, are all essential for erythropoiesis. Structural-functional and murine knock-in experiments have suggested that EPO-R Tyr-343 is important in EPO-mediated mitogenesis. Although Stat5 binds to EPO-R phosphotyrosine 343, the initial Stat5-deficient mice did not have profound erythroid abnormalities suggesting that additional Src homology 2 (SH2) domain-containing effectors may bind to EPO-R Tyr-343 and couple to downstream signaling pathways. We have utilized cloning of ligand target (COLT) screening to demonstrate that EPO-R Tyr(P)-343 and Tyr(P)-401 bind to the SH2 domain-containing adaptor protein SH2B1β. Immunoprecipitation and in vitro mixing experiments reveal that EPO-R binds to SH2B1 in an SH2 domain-dependent manner and that the sequence that confers SH2B1 binding to the EPO-R is pYXXL. Previous studies have shown that SH2B1 binds directly to JAK2, but we show that in hematopoietic cells, SH2B1β preferentially associates with the EPO-R. SH2B1 is capable of constitutive association with EPO-R, which is necessary for its optimal SH2-dependent recruitment to EPO-R-Tyr(P)-343/Tyr(P)-401. We also demonstrate that SH2B1 is responsive to EPO stimulation and becomes phosphorylated, most likely on serines/threonines, in an EPO dose- and time-dependent manner. In the absence of SH2B1, we observe enhanced activation of signaling pathways downstream of the EPO-R, indicating that SH2B1 is a negative regulator of EPO signaling.
    • References:
      J Biol Chem. 1997 May 30;272(22):14009-12. (PMID: 9162017)
      Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9126-31. (PMID: 8799165)
      Science. 1999 Feb 12;283(5404):987-90. (PMID: 9974392)
      Cell. 1998 May 1;93(3):385-95. (PMID: 9590173)
      J Biol Chem. 2002 May 10;277(19):17359-66. (PMID: 11875080)
      Blood. 2006 Jun 15;107(12):4898-906. (PMID: 16493008)
      Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7172-7. (PMID: 10377387)
      Exp Cell Res. 2005 Sep 10;309(1):1-11. (PMID: 15953601)
      Blood. 2005 Jun 15;105(12):4604-12. (PMID: 15705783)
      Mol Cell Biol. 2006 Sep;26(17):6381-94. (PMID: 16914724)
      J Biol Chem. 1999 Jul 16;274(29):20465-72. (PMID: 10400674)
      Mol Cell Biol. 2001 Mar;21(5):1613-20. (PMID: 11238898)
      Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8324-8. (PMID: 8710869)
      J Biol Chem. 2000 Nov 3;275(44):34719-27. (PMID: 10940312)
      Genes Dev. 1996 Jan 15;10(2):154-64. (PMID: 8566749)
      Blood. 2005 Jan 15;105(2):552-61. (PMID: 15213094)
      Blood. 2001 Dec 1;98(12):3261-73. (PMID: 11719363)
      J Biol Chem. 2004 Oct 15;279(42):43684-91. (PMID: 15316008)
      Blood. 1994 Sep 1;84(5):1501-7. (PMID: 8068943)
      J Biol Chem. 1997 Jun 6;272(23):14611-6. (PMID: 9169421)
      Mol Cell Biol. 2005 Apr;25(7):2607-21. (PMID: 15767667)
      Mol Cell Biol. 1994 Apr;14(4):2257-65. (PMID: 8139531)
      Mol Cell Biol. 1994 Apr;14(4):2777-85. (PMID: 7511210)
      Cell. 1999 Jul 23;98(2):181-91. (PMID: 10428030)
      Cell. 1995 Oct 6;83(1):59-67. (PMID: 7553874)
      J Cell Sci. 2011 May 1;124(Pt 9):1542-52. (PMID: 21486950)
      Mol Endocrinol. 2007 Sep;21(9):2270-81. (PMID: 17565041)
      J Biol Chem. 2000 Feb 11;275(6):4398-406. (PMID: 10660611)
      Leukemia. 1999 May;13(5):760-7. (PMID: 10374881)
      Blood. 2008 Nov 1;112(9):3878-88. (PMID: 18694996)
      Oncogene. 1998 Dec 17;17(24):3073-82. (PMID: 9872323)
      Mol Cell Biol. 2004 May;24(10):4557-70. (PMID: 15121872)
      Blood. 2006 Apr 1;107(7):2662-72. (PMID: 16332976)
      Trends Cell Biol. 2005 Mar;15(3):146-55. (PMID: 15752978)
      Blood. 2001 Apr 15;97(8):2230-7. (PMID: 11290583)
      Mol Cell Biol. 1997 Nov;17(11):6633-44. (PMID: 9343427)
      Cell. 1989 Apr 21;57(2):277-85. (PMID: 2539263)
      EMBO J. 2001 Jun 15;20(12):3156-66. (PMID: 11406592)
      Blood. 2002 Feb 1;99(3):898-904. (PMID: 11806992)
      Proc Natl Acad Sci U S A. 2006 Jan 24;103(4):1000-5. (PMID: 16418296)
      J Cell Biochem. 2008 Jan 1;103(1):162-81. (PMID: 17615553)
      Mol Cell Biol. 2000 May;20(9):3168-77. (PMID: 10757801)
      EMBO J. 1995 Nov 15;14(22):5557-68. (PMID: 8521813)
      J Biol Chem. 1998 Aug 14;273(33):21239-45. (PMID: 9694882)
      Cell. 1993 Mar 12;72(5):767-78. (PMID: 7680959)
      Trends Endocrinol Metab. 2007 Jan-Feb;18(1):38-45. (PMID: 17140804)
      Blood. 2008 Sep 1;112(5):2071-80. (PMID: 18552213)
      Mol Cell. 2001 Dec;8(6):1327-38. (PMID: 11779507)
      Blood. 2005 Apr 1;105(7):2952-4. (PMID: 15585651)
      Blood. 2003 Nov 1;102(9):3147-53. (PMID: 12869513)
      Cell. 1998 May 29;93(5):841-50. (PMID: 9630227)
      Cell. 1998 May 1;93(3):397-409. (PMID: 9590174)
      J Biol Chem. 1999 Sep 10;274(37):26485-92. (PMID: 10473609)
      J Clin Invest. 2006 Mar;116(3):683-94. (PMID: 16511603)
    • Grant Information:
      R01 DK054222 United States DK NIDDK NIH HHS; R01-DK54222 United States DK NIDDK NIH HHS; MOP-13612 Canada CAPMC CIHR
    • Accession Number:
      0 (Adaptor Proteins, Signal Transducing)
      0 (Peptide Fragments)
      0 (Receptors, Erythropoietin)
      0 (Sh2bpsm1 protein, mouse)
      11096-26-7 (Erythropoietin)
    • Publication Date:
      Date Created: 20120607 Date Completed: 20121011 Latest Revision: 20211021
    • Publication Date:
      20250114
    • Accession Number:
      PMC3406707
    • Accession Number:
      10.1074/jbc.M112.382721
    • Accession Number:
      22669948