EMBO J. 2005 Mar 23;24(6):1192-201. Epub 2005 Feb 24.

The dependence receptor UNC5H2 mediates apoptosis through DAP-kinase.External

Llambi, F., Lourenco, F. C., Gozuacik, D., Guix, C., Pays, L., Del Rio, G., Kimchi, A., Mehlen, P.,
--- - Apoptosis, Cancer and Development Laboratory, Equipe labellisee La Ligue, CNRS FRE2870, Centre Leon Berard, Lyon, France.
Netrin-1 receptors UNC5H (UNC5H1-4) were originally proposed to mediate the chemorepulsive activity of netrin-1 during axonal guidance processes. However, UNC5H receptors were more recently described as dependence receptors and, as such, able to trigger apoptosis in the absence of netrin-1. They were also proposed as putative tumor suppressors. Here, we show that UNC5H2 physically interacts with the serine/threonine kinase death-associated protein kinase (DAP-kinase) both in cell culture and in embryonic mouse brains. This interaction occurs in part through the respective death domains of UNC5H2 and DAP-kinase. Moreover, part of UNC5H2 proapoptotic activity occurs through this interaction because UNC5H2-induced cell death is partly impaired in the presence of dominant-negative mutants of DAP-kinase or in DAP-kinase mutant murine embryonic fibroblast cells. In the absence of netrin-1, UNC5H2 reduces DAP-kinase autophosphorylation on Ser308 and increases the catalytic activity of the kinase while netrin-1 blocks UNC5H2-dependent DAP-kinase activation. Thus, the pair netrin-1/UNC5H2 may regulate cell fate by controlling the proapoptotic kinase activity of DAP-kinase.
PMID: 15729359External
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vivo interaction
  Endogenous
expression
Overexpression DD1 DD2 Reference
Family DD1 DD2 Method Species Region Species Region
DD DAPK1 Link UNC5B Co-immunoprecipitation HEK293 Not specified Full length Not specified Full length 15729359
DD DAPK1 Link UNC5B Co-immunoprecipitation HEK293 Not specified Full length Not specified Not specified 15729359
DD DAPK1 Link UNC5B Co-immunoprecipitation HEK293 Not specified Full length Not specified 841-945 15729359
DD DAPK1 Link UNC5B Co-immunoprecipitation HEK293 Not specified Full length Not specified 631-945 15729359
DD DAPK1 Link UNC5B Co-immunoprecipitation HEK293 Not specified 1301-1431 Not specified Full length 15729359
(Link: click this icon to show interactions only between the two corresponding DDs)
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
Functional Role
Family DD1 DD2 Method Death-related Death-unrelated Reference
DD DAPK1 Link UNC5B Trypan blue staining, Immunoprecipitation Apoptosis, DAPK kinase activity increase 15729359
(Link: click this icon to show interactions only between the two corresponding DDs)