Evolutionary divergence in the catalytic activity of the CAM-1, ROR1 and ROR2 kinase domains.
Receptor tyrosine kinase-like orphan receptors (ROR) 1 and 2 are atypical members of the receptor tyrosine kinase (RTK) family and have been associated with several human diseases. The vertebrate RORs contain an ATP binding domain that deviates from the consensus amino acid sequence, although the im...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4100928?pdf=render |
| _version_ | 1818899970389966848 |
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| author | Travis W Bainbridge Venita I DeAlmeida Anita Izrael-Tomasevic Cécile Chalouni Borlan Pan Joshua Goldsmith Alia P Schoen Gabriel A Quiñones Ryan Kelly Jennie R Lill Wendy Sandoval Mike Costa Paul Polakis David Arnott Bonnee Rubinfeld James A Ernst |
| author_facet | Travis W Bainbridge Venita I DeAlmeida Anita Izrael-Tomasevic Cécile Chalouni Borlan Pan Joshua Goldsmith Alia P Schoen Gabriel A Quiñones Ryan Kelly Jennie R Lill Wendy Sandoval Mike Costa Paul Polakis David Arnott Bonnee Rubinfeld James A Ernst |
| author_sort | Travis W Bainbridge |
| collection | DOAJ |
| description | Receptor tyrosine kinase-like orphan receptors (ROR) 1 and 2 are atypical members of the receptor tyrosine kinase (RTK) family and have been associated with several human diseases. The vertebrate RORs contain an ATP binding domain that deviates from the consensus amino acid sequence, although the impact of this deviation on catalytic activity is not known and the kinase function of these receptors remains controversial. Recently, ROR2 was shown to signal through a Wnt responsive, β-catenin independent pathway and suppress a canonical Wnt/β-catenin signal. In this work we demonstrate that both ROR1 and ROR2 kinase domains are catalytically deficient while CAM-1, the C. elegans homolog of ROR, has an active tyrosine kinase domain, suggesting a divergence in the signaling processes of the ROR family during evolution. In addition, we show that substitution of the non-consensus residues from ROR1 or ROR2 into CAM-1 and MuSK markedly reduce kinase activity, while restoration of the consensus residues in ROR does not restore robust kinase function. We further demonstrate that the membrane-bound extracellular domain alone of either ROR1 or ROR2 is sufficient for suppression of canonical Wnt3a signaling, and that this domain can also enhance Wnt5a suppression of Wnt3a signaling. Based on these data, we conclude that human ROR1 and ROR2 are RTK-like pseudokinases. |
| first_indexed | 2024-12-19T19:56:25Z |
| format | Article |
| id | doaj.art-080290e22e094a90849ffe90a71ec97c |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-19T19:56:25Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-080290e22e094a90849ffe90a71ec97c2022-12-21T20:07:47ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0197e10269510.1371/journal.pone.0102695Evolutionary divergence in the catalytic activity of the CAM-1, ROR1 and ROR2 kinase domains.Travis W BainbridgeVenita I DeAlmeidaAnita Izrael-TomasevicCécile ChalouniBorlan PanJoshua GoldsmithAlia P SchoenGabriel A QuiñonesRyan KellyJennie R LillWendy SandovalMike CostaPaul PolakisDavid ArnottBonnee RubinfeldJames A ErnstReceptor tyrosine kinase-like orphan receptors (ROR) 1 and 2 are atypical members of the receptor tyrosine kinase (RTK) family and have been associated with several human diseases. The vertebrate RORs contain an ATP binding domain that deviates from the consensus amino acid sequence, although the impact of this deviation on catalytic activity is not known and the kinase function of these receptors remains controversial. Recently, ROR2 was shown to signal through a Wnt responsive, β-catenin independent pathway and suppress a canonical Wnt/β-catenin signal. In this work we demonstrate that both ROR1 and ROR2 kinase domains are catalytically deficient while CAM-1, the C. elegans homolog of ROR, has an active tyrosine kinase domain, suggesting a divergence in the signaling processes of the ROR family during evolution. In addition, we show that substitution of the non-consensus residues from ROR1 or ROR2 into CAM-1 and MuSK markedly reduce kinase activity, while restoration of the consensus residues in ROR does not restore robust kinase function. We further demonstrate that the membrane-bound extracellular domain alone of either ROR1 or ROR2 is sufficient for suppression of canonical Wnt3a signaling, and that this domain can also enhance Wnt5a suppression of Wnt3a signaling. Based on these data, we conclude that human ROR1 and ROR2 are RTK-like pseudokinases.http://europepmc.org/articles/PMC4100928?pdf=render |
| spellingShingle | Travis W Bainbridge Venita I DeAlmeida Anita Izrael-Tomasevic Cécile Chalouni Borlan Pan Joshua Goldsmith Alia P Schoen Gabriel A Quiñones Ryan Kelly Jennie R Lill Wendy Sandoval Mike Costa Paul Polakis David Arnott Bonnee Rubinfeld James A Ernst Evolutionary divergence in the catalytic activity of the CAM-1, ROR1 and ROR2 kinase domains. PLoS ONE |
| title | Evolutionary divergence in the catalytic activity of the CAM-1, ROR1 and ROR2 kinase domains. |
| title_full | Evolutionary divergence in the catalytic activity of the CAM-1, ROR1 and ROR2 kinase domains. |
| title_fullStr | Evolutionary divergence in the catalytic activity of the CAM-1, ROR1 and ROR2 kinase domains. |
| title_full_unstemmed | Evolutionary divergence in the catalytic activity of the CAM-1, ROR1 and ROR2 kinase domains. |
| title_short | Evolutionary divergence in the catalytic activity of the CAM-1, ROR1 and ROR2 kinase domains. |
| title_sort | evolutionary divergence in the catalytic activity of the cam 1 ror1 and ror2 kinase domains |
| url | http://europepmc.org/articles/PMC4100928?pdf=render |
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