Oncogene (2010) 29, 1865–1882 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 $32.00 www.nature.com/onc REVIEW Dependence receptors: a new paradigm in cell signaling and cancer therapy D Goldschneider and P Mehlen Apoptosis, Cancer and Development Laboratory- Equipe labellise´e ‘La Ligue’, CNRS UMR5238, Centre Le´on Be´rard, Universite´ de Lyon, Lyon, France Dependence receptors (DRs) now form a family of more (Stupack et al., 2001). All of them are involved in both than a dozen membrane receptors that are not linked by nervous system development and cancer progression. their structure, but by common functional traits. The most notable is their ability to trigger two opposite signaling pathways: in the presence of ligand, these receptors Dependence receptors: a short history activate classic signaling pathways implicated in cell survival, migration and differentiation. In the absence of Neurotrophin receptor p75NTR was the first DR to be ligand, they do not stay inactive, rather they elicit an described. P75NTR was discovered as one of two apoptotic signal. Thus, cells expressing this kind of receptors able to bind nerve growth factor (Chao receptor are dependent on the presence of ligand in the et al., 1986), the other being TrkA (Kaplan et al., extracellular environment to survive. This review will 1991). TrkA was rapidly shown to mediate the known recapitulate the increasing data regarding the molecular responses to NGF, such as neurite outgrowth and mechanisms associated with DRs, their potential implica- neuronal survival (Lee et al., 2001a; Lykissas et al., tion during development, as well as their deregulation 2007), whereas the precise biological role of p75NTR during tumorigenesis and, finally, their emergence as new remained misunderstood. p75NTR was shown to collabo- possible therapeutic targets for cancer treatment. rate with TrkA to form high-affinity sites for NGF Oncogene (2010) 29, 1865–1882; doi:10.1038/onc.2010.13; binding (Hempstead et al., 1991). In addition, p75NTR published online 22 February 2010 was shown to alter the ligand specificity of other Trk receptors. For example, brain-derived neurotrophic Keywords: dependence receptors; apoptosis; caspase; factor, NT3 and NT4/5 can all bind TrkB in the absence tumor progression; cancer therapy of p75NTR, whereas only brain-derived neurotrophic factor does so in the presence of p75NTR. In contrast, coexpression of p75NTR with TrkC results in a relaxation Membrane receptors are classically considered as inactive in its absolute specificity for NT3 (Hempstead, 2002). At unless bound to their ligand. However, increasing observa- the time of its discovery, p75NTR was considered as a tions demonstrate that some receptors, in addition to their unique type of protein but, subsequently, a large ‘positive’ signaling when their ligand is present, transduce a superfamily of tumor necrosis factor (TNF) receptors ‘negative’ signal that induces apoptosis in the absence of were found to share the overall structure of p75NTR ligand (Figure 1). Cells expressing these receptors are thus (Liepinsh et al., 1997). Identification of this superfamily dependent on the presence of ligand to survive. These helped elucidate some of the biological functions of receptors are named ‘dependence receptors.’ To date, the p75NTR, including its link to cell death regulation. The dependence receptor (DR) family is composed of more relationship between these TNF death receptors, which than a dozen members including DCC (deleted in color- induce cell death on binding of proapoptotic ligand such ectal carcinoma) (Mehlen et al., 1998), UNC5Hs (un- as TNF or FasL, and p75NTR, which binds NGF, a coordinated 5 homologs), neogenin (Matsunaga et al., trophic factor known to induce cell survival, led DE NTR 2004), p75 (p75 neurotrophin receptor) (Rabizadeh Bredesen and colleagues to propose that p75NTR induces et al., 1993), RET (rearranged during transfection) cell death when unoccupied by NGF, whereas binding (Bordeaux et al., 2000), TrkC (tyrosine kinase receptor C) of NGF blocks apoptosis (Rabizadeh et al., 1993) (Tauszig-Delamasure et al., 2007), Ptc (patched) (Thibert (Figure 2 and Table 1). This finding suggested that et al., 2003), EphA4 (ephrin type A receptor 4) (Furne p75NTR expression creates a state of cellular dependence et al., 2009), ALK (anaplastic lymphoma kinase) (Mourali on NGF. Further studies with knockout mice confirmed et al.,2006),MET(Tulasneet al., 2004) and some integrins this notion. First, p75NTR-deficient mice have an increased number of cholinergic neurons, somal hyper- Correspondence: Dr P Mehlen, Apoptosis, Cancer and Development trophy and hyperinnervation in some areas of the Laboratory- Equipe labellise´e ‘La Ligue’, CNRS UMR5238, Centre hippocampus (Yeo et al., 1997; Naumann et al., 2002). Le´on Be´rard, Universite´de Lyon, 28 rue Laennec, Lyon, Rhone 69008, In addition, crossing NGF hemizygous mice, which France. E-mail: [email protected] display a reduction in cholinergic cell numbers, with NTR NTR Received 1 October 2009; revised 2 January 2010; accepted 6 January p75 null mice showed that loss of p75 partially 2010; published online 22 February 2010 restores cholinergic cell numbers (Naumann et al., A new paradigm in cell signaling and cancer therapy D Goldschneider and P Mehlen 1866 2002). However, the overall picture of p75NTR function binding rather than ligand withdrawal (Casaccia-Bon- became more complicated when some studies showed nefil et al., 1996; Frade et al., 1996). Particularly, in that p75NTR induced apoptosis in response to ligand addition to its ability to bind mature neurotrophins, Table 1 DRs and their known ligands Receptors Ligands p75NTR NGF, proNGF, BDNF, NT-3, NT-4/5, b-amyloid, prion DCC netrin-1, netrin-4 Neogenin netrin-1, RGMa, RGMb, RGMc, netrin-3, netrin-4 Unc50s netrin-1, netrin-4 RET GDNF, neurturin, artemin, persephin Ptc Shh TrkC NT-3 EphA4 ephrinB3, ephrinA1, ephrinA4 ALK pleiotrophin, midkin, jeb Survival, MET HGF Migration, APOPTOSIS AR androgens Differentiation Integrin avb3 extracellular matrix and a5b1 Figure 1 The DR model. DRs have two faces: in the presence of their respective ligand, they transduce a positive signal of The above listed are the DRs and their known ligands. In case of differentiation, migration or survival, whereas in the absence of multiple ligands, those which were shown to block apoptotic function their ligand, they do not stay inactive but, rather, induce apoptosis. are underlined. ALK is a particular case: its putative ligands have not Thus, cells expressing such receptors are dependent on ligand yet been tested for blocking apoptosis, only agonist antibodies have availability for survival. been used. Figure 2 Representation of the DR family. The functional domains present in extra and intracellular domains are represented. DRs are not related to each other according to their structure, but according to their ability to induce apoptosis in the absence of ligand. All of them are caspase substrates, except p75NTR and integrins. The position of caspase cleavage sites is indicated. Localization of ADD, which has been more or less precisely determined depending on receptor, is indicated by double arrows. Oncogene A new paradigm in cell signaling and cancer therapy D Goldschneider and P Mehlen 1867 other cell-death-inducing ligands have been proposed embryogenesis. In vertebrates, besides netrin-1, four for p75NTR, such as pro-NGF (Lee et al., 2001b), other netrins have been described: netrin-2/3/2like, b-amyloid (Yaar et al., 2002) and prion (Della-Bianca netrin-4/b, netrin-G1 and netrin-G2 (Puschel, 1999; et al., 2001) peptides. The decision between ligand- Mehlen and Mazelin, 2003). Netrins are structurally induced apoptosis and ligand-inhibited apoptosis related to the short arm of laminin (g for netrin 1–3 and mediated by p75NTR likely depends on cell type and b for netrin-4, G1 and G2). Netrins 1–4 are secreted, development stage (Barrett and Bartlett, 1994). Because whereas netrin-G1 and G2 are membrane anchored by the idea of a receptor triggering apoptosis when means of a glycophosphatidylinol tail. Secreted netrins unbound to its ligand contradicted the dogma regarding exert their biological functions by binding to receptors receptor signaling and the trophic theory, considering such as DCC, UNC5, neogenin and DSCAM, whereas p75NTR as a classic death receptor had more success than netrin Gs do not interact with these receptors (Rajase- considering it as a DR. Consequently, DR p75NTR has kharan and Kennedy, 2009). Interestingly, netrin-5 has been rather forgotten, although it was the first to be recently appeared in databases, which seems to be described and no definitive evidence has demonstrated related to the netrin 1–3 group according to its sequence. that it is not a DR. Netrin-1 is the most studied member of the netrin family The concept reemerged with DCC. DCC was dis- and to date it seems to be the main ligand for DCC, as covered in 1990 as a putative cell-surface receptor well as for UNC5 receptors (see below), although a encoded by a gene frequently deleted through allelic recent report mentioned that netrin-4 could interact with loss in colorectal carcinoma (Fearon et al., 1990). DCC and UNC5H1 (Qin et al., 2007). Observation that DCC expression is reduced or lost in The UNC5 receptor was initially identified in colorectal cancer led to the proposal that DCC Caenorhabditis elegans as an axonal guidance trans- expression represented a constraint for disease progres- membrane receptor (Leung-Hagesteijn et al., 1992) and, sion and is therefore a tumor suppressor. This hypo- on the basis of a genetic screen, was predicted to interact thesis was supported by the fact that DCC expression is with UNC6 (the C. elegans netrin-1 ortholog) (Hedge- lost or reduced in various cancers (Mehlen and Fearon, cock et al., 1990). Four homologs of UNC5 have been 2004) and that its loss of expression is associated with described in mammals (UNC5H1, 2, 3 and 4 in rodents poor prognosis (Shibata et al., 1996; Sun et al., 1999).