The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis

Elena Rivkin, Stephanie M. Almeida, Derek F. Ceccarelli, Yu-Chi Juang, Teresa A. MacLean, Tharan Srikumar, Hao Huang, Wade H. Dunham, Ryutaro Fukumura, Gang Xie, Yoichi Gondo, Brian Raught, Anne-Claude Gingras, Frank Sicheri () and Sabine P. Cordes ()
Additional contact information
Elena Rivkin: Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
Stephanie M. Almeida: Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
Derek F. Ceccarelli: Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
Yu-Chi Juang: Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
Teresa A. MacLean: Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
Tharan Srikumar: University of Toronto and Ontario Cancer Institute, Princess Margaret Cancer Centre, Toronto, Ontario M5G 1L7, Canada
Hao Huang: Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
Wade H. Dunham: Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
Ryutaro Fukumura: Mutagenesis and Genomics Team, RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan
Gang Xie: Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
Yoichi Gondo: Mutagenesis and Genomics Team, RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan
Brian Raught: University of Toronto and Ontario Cancer Institute, Princess Margaret Cancer Centre, Toronto, Ontario M5G 1L7, Canada
Anne-Claude Gingras: Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
Frank Sicheri: Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
Sabine P. Cordes: Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada

Nature, 2013, vol. 498, issue 7454, 318-324

Abstract: Abstract A complex interaction of signalling events, including the Wnt pathway, regulates sprouting of blood vessels from pre-existing vasculature during angiogenesis. Here we show that two distinct mutations in the (uro)chordate-specific gumby (also called Fam105b) gene cause an embryonic angiogenic phenotype in gumby mice. Gumby interacts with disheveled 2 (DVL2), is expressed in canonical Wnt-responsive endothelial cells and encodes an ovarian tumour domain class of deubiquitinase that specifically cleaves linear ubiquitin linkages. A crystal structure of gumby in complex with linear diubiquitin reveals how the identified mutations adversely affect substrate binding and catalytic function in line with the severity of their angiogenic phenotypes. Gumby interacts with HOIP (also called RNF31), a key component of the linear ubiquitin assembly complex, and decreases linear ubiquitination and activation of NF-κB-dependent transcription. This work provides support for the biological importance of linear (de)ubiquitination in angiogenesis, craniofacial and neural development and in modulating Wnt signalling.

Date: 2013
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DOI: 10.1038/nature12296

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