Abstract
The recently described family of dependence receptors is a new family of functionally related receptors. These proteins have little sequence similarity but display the common feature of inducing two completely opposite intracellular signals depending on ligand availability: in the presence of ligand, these receptors transduce a positive signal leading to survival, differentiation or migration, while in the absence of ligand, the receptors initiate or amplify a negative signal for apoptosis. Thus, cells that express these proteins manifest a state of dependence on their respective ligands. The mechanisms that trigger cell death induction in the absence of ligand are in large part unknown, but typically require cleavage by specific caspases. In this review we will present the proposed mechanisms for cell death induction by these receptors and their potential function in nervous system development and regulation of tumorigenesis.
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Rabizadeh S., Oh J., Zhong L. T., Yang J., Bider C. M., Butcher L. L. et al. (1993) Induction of apoptosis by the low-affinity NGF receptor. Science 261(5119): 345–348
Mehlen P., Rabizadeh S., Snipas S. J., Assa-Munt N., Salvesen G. S. and Bredesen D. E. (1998) The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis. Nature 395(6704): 801–804
Llambi F., Causeret F., Bloch-Gallego E. and Mehlen P. (2001) Netrin-1 acts as a survival factor via its receptors UNC5H and DCC. EMBO J. 20(11): 2715–2722
Ellerby L. M., Hackam A. S., Propp S. S., Ellerby H. M., Rabizadeh S., Cashman N. R. et al. (1999) Kennedy's disease: caspase cleavage of the androgen receptor is a crucial event in cytotoxicity. J. Neurochem. 72(1): 185–195
Bordeaux M. C., Forcet C., Granger L., Corset V., Bidaud C., Billaud M. et al. (2000) The RET proto-oncogene induces apoptosis: a novel mechanism for Hirschsprung disease. EMBO J. 19(15): 4056–4063
Stupack D. G., Puente X. S., Boutsaboualoy S., Storgard C. M. and Cheresh D. A. (2001) Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins. J. Cell Biol. 155(3): 459–470
Ruoslahti E. and Reed J. C. (1994) Anchorage dependence, integrins and apoptosis. Cell 77(4): 477–478
Thibert C., Teillet M. A., Lapointe F., Mazelin L., Le Douarin N. M. and Mehlen P. (2003) Inhibition of neuroepithelial patched-induced apoptosis by sonic hedgehog. Science 301(5634): 843–846
Levi-Montalcini R. (1966) The nerve growth factor: its mode of action on sensory and sympathetic nerve cells. Harvey Lect. 60: 217–259
Chao M. V., Bothwell M. A., Ross A. H., Koprowski H., Lanahan A. A., Buck C. R. et al. (1986) Gene transfer and molecular cloning of the human NGF receptor. Science 232(4749): 518–521.
Radeke M. J., Misko T. P., Hsu C., Herzenberg L. A. and Shooter E. M. (1987) Gene transfer and molecular cloning of the rat nerve growth factor receptor. Nature 325(6105): 593–597
Hempstead B. L., Martin-Zanca D., Kaplan D. R., Parada L. F. and Chao M. V. (1991) High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor. Nature 350(6320): 678–683
Ibanez C. F. (1994) Structure-function relationships in the neurotrophin family. J. Neurobiol. 25(11): 1349–1361
Lee F. S., Kim A. H., Khursigara G. and Chao M. V (2001) The uniqueness of being a neurotrophin receptor. Curr. Opin. Neurobiol. 11(3): 281–286
Verdi J. M., Birren S. J., Ibanez C. F., Persson H., Kaplan D. R., Benedetti M. et al. (1994) p75LNGFR regulates Trk signal transduction and NGF-induced neuronal differentiation in MAH cells. Neuron 12(4): 733–745
Chao M. V (1994) The p75 neurotrophin receptor. J. Neurobiol. 25(11): 1373–1385
Barrett G. L. and Bartlett P. F. (1994) The p75 nerve growth factor receptor mediates survival or death depending on the stage of sensory neuron development. Proc. Natl. Acad. Sci. USA 91(14): 6501–6505
Rabizadeh S. and Bredesen D. E. (2003) Ten years on: mediation of cell death by the common neurotrophin receptor p75(NTR). Cytokine Growth Factor Rev. 14(3–4): 225–239
Yeo T. T., Chua-Couzens J., Butcher L. L., Bredesen D. E., Cooper J. D., Valletta J. S. et al. (1997) Absence of p75NTR causes increased basal forebrain cholinergic neuron size, choline acetyltransferase activity and target innervation. J. Neurosci. 17(20): 7594–7605
Naumann T., Casademunt E., Hollerbach E., Hofmann J., Dechant G., Frotscher M. et al. (2002) Complete deletion of the neurotrophin receptor p75NTR leads to long-lasting increases in the number of basal forebrain cholinergic neurons. J. Neurosci. 22(7): 2409–2418
Sauer H., Nishimura M. C. and H. S. P. (1996) Deletion of the p75NTR gene attenuates septal cholinergic cell loss in mice heterozygous for a deletion of the NGF gene. Soc. Neurosci. Abs. (22): 513–514
Casaccia-Bonnefil P., Carter B. D., Dobrowsky R. T. and Chao M. V (1996) Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature 383(6602):716–719
Frade J. M., Rodriguez-Tebar A. and Barde Y. A. (1996) Induction of cell death by endogenous nerve growth factor through its p75 receptor. Nature 383(6596): 166–168
Bredesen D. E. and Rabizadeh S. (1997) p75NTR and apoptosis: Trk-dependent and Trk-independent effects. Trends Neurosci. 20(7): 287–290
Bredesen D. E., Ye X., Tasinato A., Sperandio S., Wang J. J., Assa-Munt N. et al. (1998) p75NTR and the concept of cellular dependence: seeing how the other half die. Cell Death Differ. 5(5): 365–371
Majdan M., Walsh G. S., Aloyz R. and Miller E D. (2001) TrkA mediates developmental sympathetic neuron survival in vivo by silencing an ongoing p75NTR-mediated death signal. J. Cell Biol. 155(7): 1275–1285
Fearon E. R., Cho K. R., Nigro J. M., Kern S. E., Simons J. W., Ruppert J. M. et al. (1990) Identification of a chromosome 18q gene that is altered in colorectal cancers. Science 247(4938):49–56
Serafini T., Kennedy T. E., Galko M. J., Mirzayan C., Jessell T. M. and Tessier-Lavigne M. (1994) The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6. Cell 78(3): 409–424
Serafini T., Colamarino S. A., Leonardo E. D., Wang H., Beddington R., Skarnes W. C. et al. (1996) Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell 87(6): 1001–1014
de la Torre J. R., Hopker V. H., Ming G. L., Poo M. M., Tessier-Lavigne M., Hemmati-Brivanlou A. et al. (1997) Turning of retinal growth cones in a netrin-1 gradient mediated by the netrin receptor DCC. Neuron 19(6): 1211–1224
Colamarino S. A. and Tessier-Lavigne M. (1995) The axonal chemoattractant netrin-1 is also a chemorepellent for trochlear motor axons. Cell 81(4): 621–629
Mehlen P. and Mazelin L. (2003) The dependence receptors DCC and UNC5H as a link between neuronal guidance and survival. Biol. Cell 95: 425–436
Cho K. R., Oliner J. D., Simons J. W., Hedrick L., Fearon E. R., Preisinger A. C. et al. (1994) The DCC gene: structural analysis and mutations in colorectal carcinomas. Genomics 19(3): 525–531
Vogelstein B., Fearon E. R., Hamilton S. R., Kern S. E., Preisinger A. C., Leppert M. et al. (1988) Genetic alterations during colorectal-tumor development. N. Engl. J. Med. 319(9): 525–532
Vogelstein B., Fearon E. R., Kern S. E., Hamilton S. R., Preisinger A. C., Nakamura Y et al. (1989) Allelotype of colorectal carcinomas. Science 244(4901): 207–211
Fearon E. R. and Vogelstein B. (1990) A genetic model for colorectal tumorigenesis. Cell 61(5): 759–767
Mehlen P. and Fearon E. R. Role of the dependence receptor DCC in colorectal cancer pathogenesis. J. Clin. Oncology, in press.
Sato K., Tamura G., Tsuchiya T., Endoh Y., Usuba O., Kimura W. et al. (2001) Frequent loss of expression without sequence mutations of the DCC gene in primary gastric cancer. Br. J. Cancer 85(2): 199–203
Fearon E. R. (1996) DCC: is there a connection between tumorigenesis and cell guidance molecules? Biochim. Biophys. Acta 1288(2): M17–23
Shibata D., Reale M. A., Lavin P., Silverman M., Fearon E. R., Steele G., Jr et al. (1996) The DCC protein and prognosis in colorectal cancer. N. Engl. J. Med. 335(23): 1727–1732
Sun X. F., Rutten S., Zhang H. and Nordenskjold B. (1999) Expression of the deleted in colorectal cancer gene is related to prognosis in DNA diploid and low proliferative colorectal adenocarcinoma. J. Clin. Oncol. 17(6): 1745–1750
Klingelhutz A. J., Smith P. P., Garrett L. R. and McDougall J. K. (1993) Alteration of the DCC tumor-suppressor gene in tumorigenic HPV 18 immortalized human keratinocytes transformed by nitrosomethylurea. Oncogene 8(1): 95–99
Velcich A., Corner G., Palumbo L. and Augenlicht L. (1999) Altered phenotype of HT29 colonic adenocarcinoma cells following expression of the DCC gene. Oncogene 18(16): 2599–606.
Riggins G. J., Thiagalingam S., Rozenblum E., Weinstein C. L., Kern S. E., Hamilton S. R. et al. (1996) Mad-related genes in the human. Nat. Genet. 13(3): 347–349
Thiagalingam S., Lengauer C., Leach E S., Schutte M., Hahn S. A., Overhauser J. et al. (1996) Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers. Nat. Genet. 13(3): 343–346
Fazeli A., Dickinson S. L., Hermiston M. L., Tighe R. V., Steen R. G., Small C. G. et al. (1997) Phenotype of mice lacking functional Deleted in colorectal cancer (Dcc) gene. Nature 386(6627):796–804
Chen Y Q., Hsieh J. T., Yao F., Fang B., Pong R. C., Cipriano S. C. et al. (1999) Induction of apoptosis and G2/M cell cycle arrest by DCC. Oncogene 18(17): 2747–2754
Forcet C., Ye X., Granger L., Corset V, Shin H., Bredesen D. E. et al. (2001) The dependence receptor DCC (deleted in colorectal cancer) defines an alternative mechanism for caspase activation. Proc. Natl. Acad. Sci. USA 98(6): 3416–3421
Liu J., Yao F., Wu R., Morgan M., Thorburn A., Finley R. L., Jr et al. (2002) Mediation of the DCC apoptotic signal by DIP13 alpha. J. Biol. Chem. 277(29): 26281–26285
Hedgecock E. M., Culotti J. G. and Hall D. H. (1990) The unc-5, unc-6 and unc-40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. elegans. Neuron 4(1): 61–85
Chan S. S., Zheng H., Su M. W., Wilk R., Killeen M. T., Hedgecock E. M. et al. (1996) UNC-40, a C. elegans homolog of DCC (Deleted in Colorectal Cancer), is required in motile cells responding to UNC-6 netrin cues. Cell 87(2): 187–195
Leonardo E. D., Hinck L., Masu M., Keino-Masu K., Ackerman S. L. and Tessier-Lavigne M. (1997) Vertebrate homologues of C. elegans UNC-5 are candidate netrin receptors. Nature 386(6627): 833–838
Hong K., Hinck L., Nishiyama M., Poo M. M., Tessier-Lavigne M. and Stein E. (1999) A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts netrin-induced growth cone attraction to repulsion. Cell 97(7): 927–941
Tanikawa C., Matsuda K., Fukuda S., Nakamura Y. and Arakawa H. (2003) p53RDL1 regulates p53-dependent apoptosis. Nat. Cell Biol. 5(3): 216–223
Takahashi M. and Cooper G. M. (1987) ret transforming gene encodes a fusion protein homologous to tyrosine kinases. Mol. Cell. Biol. 7(4): 1378–1385
Takeichi M. (1991) Cadherin cell adhesion receptors as a morphogenetic regulator. Science 251(5000): 1451–1455
Manic S., Santoro M., Fusco A. and Billaud M. (2001) The RET receptor: function in development and dysfunction in congenital malformation. Trends. Genet. 17(10): 580–589
Baloh R. H., Tansey M. G., Golden J. P., Creedon D. J., Heuckeroth R. O., Keck C. L. et al. (1997) Milbrandt J. TmR2, a novel receptor that mediates neurturin and GDNF signaling through Ret. Neuron 18(5): 793–802
Schuchardt A., D'Agati V., Larsson-Blomberg L., Costantini F. and Pachnis V. (1994) Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367(6461): 380–383
Sanchez M. P., Silos-Santiago I., Frisen J., He B., Lira S. A. and Barbacid M. (1996) Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382(6586): 70–73
Cacalano G., Farinas I., Wang L. C., Hagler K., Forgie A., Moore M. et al. (1998) GFRalphal is an essential receptor component for GDNF in the developing nervous system and kidney. Neuron 21(1): 53–62
Mulligan L. M., Kwok J. B., Healey C. S., Elsdon M. J., Eng C., Gardner E. et al. (1993) Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363(6428): 458–460
Romeo G., Ronchetto P., Luo Y., Barone V., Seri M., Ceccherini I. et al. (1994) Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease. Nature 367(6461): 377–378
Pasini B., Ceccherini I. and Romeo G. (1996) RET mutations in human disease. Trends Genet. 12(4): 138–144
Stupack D. G. and Cheresh D. A. (2002) Get a ligand, get a life: integrins, signaling and cell survival. J. Cell Sci. 115(Pt 19):3729–3738
Hood J. D. and Cheresh D. A. (2002) Role of integrins in cell invasion and migration. Nat. Rev. Cancer ) 2(2): 91–100
Jessell T. M. (2000) Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nat. Rev. Genet. 1(1): 20–29
Murone M., Rosenthal A. and de Sauvage E J. (1999) Sonic hedgehog signaling by the patched-smoothened receptor complex. Curr. Biol. 9(2): 76–84
Ingham P. W. and McMahon A. P (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 15(23):3059–3087
Marigo V., Davey R. A., Zuo Y., Cunningham J. M. and Tabin C. J. (1996) Biochemical evidence that patched is the Hedgehog receptor. Nature 384(6605): 176–179
Stone D. M., Hynes M., Armanini M., Swanson T. A., Gu Q., Johnson R. L. et al. (1996) The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 384(6605): 129–134
Taipale J., Cooper M. K., Maiti T. and Beachy P A. (2002) Patched acts catalytically to suppress the activity of Smoothened. Nature 418(6900): 892–897
Charrier J. B., Teillet M. A., Lapointe F. and Le Douarin N. M. (1999) Defining subregions of Hensen's node essential for caudalward movement, midline development and cell survival. Development 126(21): 4771–4783
Charrier J. B., Lapointe F., Le Douarin N. M. and Teillet M. A. (2001) Anti-Aopotic role of Sonic hedgehog protein at the early stages of nervous system organogenesis. Development 128(20):4011–4020
Wicking C. and McGlinn E. (2001) The role of hedgehog signalling in tumorigenesis. Cancer Lett. 173(1): 1–7
Lee D. K. and Chang C. (2003) Molecular communication between androgen receptor and general transcription machinery. J. Steroid Biochem. Mol. Biol. 84(1): 41–49
Clark P. E., Irvine R. A. and Coetzee G. A. (2003) The androgen receptor CAG repeat and prostate cancer risk. Methods Mol. Med. 81: 255–266
La Spada A. R., Wilson E. M., Lubahn D. B., Harding A. E. and Fischbeck K. H. (1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352(6330):77–79
Fischbeck K. H. (1997) Kennedy disease. J. Inherit. Metab. Dis. 20(2): 152–158
Zupan A. A. and Johnson E. M., Jr (1991) Evidence for endocytosis-dependent proteolysis in the generation of soluble truncated nerve growth factor receptors by A875 human melanoma cells. J. Biol. Chem. 266(23): 15384–15390
Kanning K. C, Hudson M., Amieux P. S., Wiley J. C., Bothwell M. and Schecterson L. C. (2003) Proteolytic processing of the p75 neurotrophin receptor and two homologs generates C-terminal fragments with signaling capability. J. Neurosci. 23(13): 5425–5436
Hofinann K. and Tschopp J. (1995) The death domain motif found in Fas (Apo-1) and TNT receptor is present in proteins involved in apoptosis and axonal guidance. FEBS Lett. 371(3): 321–323
Rabizadeh S., Ye X., Sperandio S., Wang J. J., Ellerby H. M., Ellerby L. M. et al. (2000) Neurotrophin dependence domain: a domain required for the mediation of apoptosis by the p75 neurotrophin receptor. J. Mol. Neurosci. 15(3): 215–229
Coulson E. J., Reid K., Baca M., Shipham K. A., Hulett S. M., Kilpatrick T. J. et al. (2000) Chopper, a new death domain of the p75 neurotrophin receptor that mediates rapid neuronal cell death. J. Biol. Chem. 275(39): 30537–30545
Williams M. E., Strickland P., Watanabe K. and Hinck L. (2003) UNC5H1 induces apoptosis via its juxtamembrane domain through an interaction with NRAGE. J. Biol. Chem.
Salehi A. H., Roux P. P., Kubu C. J., Zeindler C., Bhakar A., Tannis L. L. et al. (2000) NRAGE, a novel MAGE protein, interacts with the p75 neurotrophin receptor and facilitates nerve growth factor-dependent apoptosis. Neuron 27(2): 279–288
Wang J. J., Rabizadeh S., Tasinato A., Sperandio S., Ye X., Green M. et al. (2000) Dimerization-dependent block of the proapoptotic effect of p75(NTR). J. Neurosci. Res. 60(5): 587–593
Stein E., Zou Y., Poo M. and Tessier-Lavigne M. (2001) Binding of DCC by netrin-1 to mediate axon guidance independent of adenosine A2B receptor activation. Science 291(5510): 1976–1982
Salvesen G. S. and Dixit V. M. (1997) Caspases: intracellular signaling by proteolysis. Cell 91(4): 443–446
Yang X., Chang H. Y. and Baltimore D. (1998) Autoproteolytic activation of pro-caspases by oligomerization. Mol. Cell. 1(2): 319–325
Salvesen G. S. and Duckett C. S. (2002) IAP proteins: blocking the road to death's door. Nat. Rev. Mol. Cell. Biol. 3(6): 401–410
Fernando P., Kelly J. F., Balazsi K., Slack R. S. and Megeney L. A. (2002) Caspase 3 activity is required for skeletal muscle differentiation. Proc. Natl. Acad. Sci. USA 99(17): 11025–11030
Campbell D. S. and Holt C. E. (2003) Apoptotic pathway and MAPKs differentially regulate chemotropic responses of retinal growth cones. Neuron 37(6): 939–952
Keino-Masu K., Masu M., Hinck L., Leonardo E. D., Chan S. S., Culotti J. G. et al. (1996) Deleted in Colorectal Cancer (DCC) encodes a netrin receptor. Cell 87(2): 175–185
Bloch-Gallego E., Ezan F., Tessier-Lavigne M. and Sotelo C. (1999) Floor plate and netrin-1 are involved in the migration and survival of inferior olivary neurons. J. Neurosci. 19(11): 4407–4420
Yee K. T., Simon H. H., Tessier-Lavigne M., O'Leary D. M. (1999) Extension of long leading processes and neuronal migration in the mammalian brain directed by the chemoattractant netrin-1. Neuron 24(3): 607–622
Jiang Y., Min-tsai L. and Gershon M. D. (2003) Netrins and DCC in the guidance of migrating neural Crest-Derived Cells in the developing bowel and pancreas. Dev. Biol. 258: 364–384
Pelet A., Geneste O., Edery P., Pasini A., Chappuis S., Atti T. et al. (1998) Various mechanisms cause RET mediated signaling defects in Hirschsprung's disease. J. Clin. Invest. 101(6): 1415–1423
Charron F., Stein E., Jeong J., McMahon A. P. and Tessier-Lavigne M. (2003) The morphogen Sonic Hedgehog is an axonal chemoattractant that collaborates with netrin-1 in midline axon guidance. Cell 113(1): 11–23
Wang K. C., Kim J. A., Sivasankaran R., Segal R. and He Z. (2002) P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420(6911): 74–78
Hopker V. H., Shewan D., Tessier-Lavigne M., Poo M. and Holt C. (1999) Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1. Nature 401(6748): 69–73
Pasterkamp R. J., Peschon J. J, Spriggs M. K. and Kolodkin A. L. (2003) Semaphorin 7A promotes axon outgrowth through integrins and MAPKs. Nature 424(6947): 398–405
Giovannucci E., Stampfer M. J., Krithivas K., Brown M., Dahl D., Brufsky A. et al. (1997) The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc. Natl. Acad. Sci. USA 94(7): 3320–3323
Pflug B. R., Onoda M., Lynch J. H. and Djakiew D. (1992) Reduced expression of the low affinity nerve growth factor receptor in benign and malignant human prostate tissue and loss of expression in four human metastatic prostate tumor cell lines. Cancer Res. 52(19): 5403–5406
Ookawa K., Sakamoto M., Hirohashi S., Yoshida Y., Sugimura T., Terada M. et al. (1993) Concordant p53 and DCC alterations and allelic losses on chromosomes 13q and 14q associated with liver metastases of colorectal carcinoma. Int. J. Cancer 53(3): 382–387
Koike C., Mizutani T., Ito T., Shimizu Y., Yamamichi N., Kameda T. et al. (2002) Introduction of wild-type patched gene suppresses the oncogenic potential of human squamous cell carcinoma cell lines including A431. Oncogene 21(17): 2670–2678
Oro A. E., Higgins K. M., Hu Z., Bonifas J. M., Epstein E. H., Jr and Scott M. P (1997) Basal cell carcinomas in mice overexpressing sonic hedgehog. Science 276(5313): 817–821
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Mehlen, P., Thibert, C. Dependence receptors: between life and death. Cell. Mol. Life Sci. 61, 1854–1866 (2004). https://doi.org/10.1007/s00018-004-3467-7
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DOI: https://doi.org/10.1007/s00018-004-3467-7