Symmetric Signaling by an Asymmetric 1 Erythropoietin: 2 Erythropoietin Receptor Complex
Via sites 1 and 2, erythropoietin binds asymmetrically to two identical receptor monomers, although it is unclear how asymmetry affects receptor activation and signaling. Here we report the design and validation of two mutant erythropoietin receptors that probe the role of individual members of the...
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| Format: | Article |
| Language: | en_US |
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Elsevier
2015
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| Online Access: | http://hdl.handle.net/1721.1/96330 https://orcid.org/0000-0002-3320-3969 https://orcid.org/0000-0002-7029-7415 |
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| author | Zhang, Yingxin L. Radhakrishnan, Mala L. Lu, Xiaohui Gross, Alec W. Tidor, Bruce Lodish, Harvey F |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Zhang, Yingxin L. Radhakrishnan, Mala L. Lu, Xiaohui Gross, Alec W. Tidor, Bruce Lodish, Harvey F |
| author_sort | Zhang, Yingxin L. |
| collection | MIT |
| description | Via sites 1 and 2, erythropoietin binds asymmetrically to two identical receptor monomers, although it is unclear how asymmetry affects receptor activation and signaling. Here we report the design and validation of two mutant erythropoietin receptors that probe the role of individual members of the receptor dimer by selectively binding either site 1 or site 2 on erythropoietin. Ba/F3 cells expressing either mutant receptor do not respond to erythropoietin, but cells co-expressing both receptors respond to erythropoietin by proliferation and activation of the JAK2-Stat5 pathway. A truncated receptor with only one cytosolic tyrosine (Y343) is sufficient for signaling in response to erythropoietin, regardless of the monomer on which it is located. Similarly, only one receptor in the dimer needs a juxtamembrane hydrophobic L253 or W258 residue, essential for JAK2 activation. We conclude that despite asymmetry in the ligand-receptor interaction, both sides are competent for signaling, and appear to signal equally. |
| first_indexed | 2024-09-23T13:47:38Z |
| format | Article |
| id | mit-1721.1/96330 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:47:38Z |
| publishDate | 2015 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/963302022-10-01T17:10:33Z Symmetric Signaling by an Asymmetric 1 Erythropoietin: 2 Erythropoietin Receptor Complex Zhang, Yingxin L. Radhakrishnan, Mala L. Lu, Xiaohui Gross, Alec W. Tidor, Bruce Lodish, Harvey F Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemistry Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Whitehead Institute for Biomedical Research Zhang, Yingxin L. Radhakrishnan, Mala L. Lu, Xiaohui Gross, Alec W. Tidor, Bruce Lodish, Harvey F. Via sites 1 and 2, erythropoietin binds asymmetrically to two identical receptor monomers, although it is unclear how asymmetry affects receptor activation and signaling. Here we report the design and validation of two mutant erythropoietin receptors that probe the role of individual members of the receptor dimer by selectively binding either site 1 or site 2 on erythropoietin. Ba/F3 cells expressing either mutant receptor do not respond to erythropoietin, but cells co-expressing both receptors respond to erythropoietin by proliferation and activation of the JAK2-Stat5 pathway. A truncated receptor with only one cytosolic tyrosine (Y343) is sufficient for signaling in response to erythropoietin, regardless of the monomer on which it is located. Similarly, only one receptor in the dimer needs a juxtamembrane hydrophobic L253 or W258 residue, essential for JAK2 activation. We conclude that despite asymmetry in the ligand-receptor interaction, both sides are competent for signaling, and appear to signal equally. National Institutes of Health (U.S.) (Grant P01 HL32262) Amgen Inc. (Research Grant) National Institutes of Health (U.S.) (Grant GM 065418) United States. Dept. of Energy. Computational Science Graduate Fellowship (DE-FG02-97ER25308) National Institutes of Health (U.S.). Ruth L. Kirschstein National Research Service Award (Postdoctoral Fellowship 5F32HL077036) 2015-04-02T16:30:00Z 2015-04-02T16:30:00Z 2009-01 2008-09 Article http://purl.org/eprint/type/JournalArticle 10972765 1097-4164 http://hdl.handle.net/1721.1/96330 Zhang, Yingxin L., Mala L. Radhakrishnan, Xiaohui Lu, Alec W. Gross, Bruce Tidor, and Harvey F. Lodish. “Symmetric Signaling by an Asymmetric 1 Erythropoietin: 2 Erythropoietin Receptor Complex.” Molecular Cell 33, no. 2 (January 2009): 266–274. © 2009 Elsevier Inc. https://orcid.org/0000-0002-3320-3969 https://orcid.org/0000-0002-7029-7415 en_US http://dx.doi.org/10.1016/j.molcel.2008.11.026 Molecular Cell Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Elsevier Elsevier |
| spellingShingle | Zhang, Yingxin L. Radhakrishnan, Mala L. Lu, Xiaohui Gross, Alec W. Tidor, Bruce Lodish, Harvey F Symmetric Signaling by an Asymmetric 1 Erythropoietin: 2 Erythropoietin Receptor Complex |
| title | Symmetric Signaling by an Asymmetric 1 Erythropoietin: 2 Erythropoietin Receptor Complex |
| title_full | Symmetric Signaling by an Asymmetric 1 Erythropoietin: 2 Erythropoietin Receptor Complex |
| title_fullStr | Symmetric Signaling by an Asymmetric 1 Erythropoietin: 2 Erythropoietin Receptor Complex |
| title_full_unstemmed | Symmetric Signaling by an Asymmetric 1 Erythropoietin: 2 Erythropoietin Receptor Complex |
| title_short | Symmetric Signaling by an Asymmetric 1 Erythropoietin: 2 Erythropoietin Receptor Complex |
| title_sort | symmetric signaling by an asymmetric 1 erythropoietin 2 erythropoietin receptor complex |
| url | http://hdl.handle.net/1721.1/96330 https://orcid.org/0000-0002-3320-3969 https://orcid.org/0000-0002-7029-7415 |
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