The dependence receptor DCC requires lipid raft localization for cell death signaling.
DCC (deleted in colorectal cancer) is a putative tumor suppressor gene whose expression is lost in numerous cancers. DCC also encodes the main receptor for the neuronal navigation cue netrin-1. It has been shown that DCC belongs to the so-called family of dependence receptors. Such receptors induce apoptosis when their ligand is absent, thus conferring a state of cellular dependence on ligand availability. We recently proposed that DCC is a tumor suppressor because it induces the death of tumor cells that grow in settings of ligand unavailability. Moreover, it seems that the DCC/netrin-1 pair may also regulate neuron survival during nervous system development. However, the mechanisms by which DCC triggers cell death are still unknown. We show here that the localization of DCC to lipid rafts is a prerequisite for its proapoptotic activity, both in immortalized cells and in primary neurons. The presence of DCC in lipid rafts probably allows the formation of an adequate submembrane complex, because the interaction of caspase-9 with DCC is inhibited by the disorganization of lipid rafts. Thus, dependence receptors may require lipid raft localization for cell death signaling.
Furne
Céline
C
Apoptosis, Cancer, and Development Laboratory, Equipe la Ligue, Centre National de la Recherche Scientifique Formation de Recherche en Evolution 2870 (CNRS FRE 2870), Centre Léon Berard, 69008 Lyon, France.
Corset
Véronique
V
Hérincs
Zoltán
Z
Cahuzac
Nathalie
N
Hueber
Anne-Odile
AO
Mehlen
Patrick
P
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D000075389:DCC Receptor; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism; D000075388:Netrin-1; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D000075389:DCC Receptor; C501909:DCC protein, human; C501912:Dcc protein, rat; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617354:Ntn1 protein, rat; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; C506433:CASP9 protein, human; C506435:Casp9 protein, rat; D053453:Caspase 9; D020169:Caspases