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The deleted in brachydactyly B domain of ROR2 is required for receptor activation by recruitment of Src

Akbarzadeh, Shiva and Wheldon, Lee M and Sweet, Steve M. M and Talma, Sonia and Mardakheh, Faraz Khosravi and Heath, John K (2008) The deleted in brachydactyly B domain of ROR2 is required for receptor activation by recruitment of Src. PLoS ONE, 3 (3). e1873. ISSN 1932-6203

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URL of Published Version: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001873

Identification Number/DOI: 10.1371/journal.pone.0001873

The transmembrane receptor 'ROR2' resembles members of the receptor tyrosine kinase family of signalling receptors in sequence but its' signal transduction mechanisms remain enigmatic. This problem has particular importance because mutations in ROR2 are associated with two human skeletal dysmorphology syndromes, recessive Robinow Syndrome (RS) and dominant acting Brachydactyly type B (BDB). Here we show, using a constitutive dimerisation approach, that ROR2 exhibits dimerisation-induced tyrosine kinase activity and the ROR2 C-terminal domain, which is deleted in BDB, is required for recruitment and activation of the non-receptor tyrosine kinase Src. Native ROR2 phosphorylation is induced by the ligand Wnt5a and is blocked by pharmacological inhibition of Src kinase activity. Eight sites of Src-mediated ROR2 phosphorylation have been identified by mass spectrometry. Activation via tyrosine phosphorylation of ROR2 receptor leads to its internalisation into Rab5 positive endosomes. These findings show that BDB mutant receptors are defective in kinase activation as a result of failure to recruit Src.

Type of Work:Article
Date:2008 (Publication)
School/Faculty:Colleges (2008 onwards) > College of Life & Environmental Sciences
Subjects:RB Pathology
QH301 Biology
Institution:University of Birmingham
Copyright Holders:Cancer Research UK
ID Code:99
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