Proteasomal degradation of Nck1 but not Nck2 regulates RhoA activation and actin dynamics

Lisa Buvall, Priyanka Rashmi, Esther Lopez-Rivera, Svetlana Andreeva, Astrid Weins, Hanna Wallentin, Anna Greka () and Peter Mundel ()
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Lisa Buvall: Harvard Medical School, Massachusetts General Hospital
Priyanka Rashmi: Harvard Medical School, Massachusetts General Hospital
Esther Lopez-Rivera: Mount Sinai School of Medicine
Svetlana Andreeva: Harvard Medical School, Massachusetts General Hospital
Astrid Weins: Harvard Medical School, Massachusetts General Hospital
Hanna Wallentin: Harvard Medical School, Massachusetts General Hospital
Anna Greka: Harvard Medical School, Massachusetts General Hospital
Peter Mundel: Harvard Medical School, Massachusetts General Hospital

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: Abstract The ubiquitously expressed adapter proteins Nck1/2 interact with a multitude of effector molecules to regulate diverse cellular functions including cytoskeletal dynamics. Here we show that Nck1, but not Nck2, is a substrate of c-Cbl-mediated ubiquitination. We uncover lysine 178 in Nck1 as the evolutionarily conserved ubiquitin acceptor site. We previously reported that synaptopodin, a proline-rich actin-binding protein, induces stress fibres by blocking the Smurf1-mediated ubiquitination of RhoA. We now find that synaptopodin competes with c-Cbl for binding to Nck1, which prevents the ubiquitination of Nck1 by c-Cbl. Gene silencing of c-Cbl restores Nck1 protein abundance and stress fibres in synaptopodin knockdown cells. Similarly, expression of c-Cbl-resistant Nck1(K178R) or Nck2 containing the SH3 domain 2 of Nck1 restores stress fibres in synaptopodin-depleted podocytes through activation of RhoA signalling. These findings reveal proteasomal regulation as a key factor in the distinct and non-redundant effects of Nck on RhoA-mediated actin dynamics.

Date: 2013
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DOI: 10.1038/ncomms3863

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