Dependence receptor

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In cellular biology, dependence receptors are proteins that mediate programmed cell death by monitoring the absence of certain trophic factors (or, equivalently, the presence of anti-trophic factors) that otherwise serve as ligands (interactors) for the dependence receptors. [1] A trophic ligand is a molecule whose protein binding stimulates cell growth, differentiation, and/or survival. [2] Cells depend for their survival on stimulation that is mediated by various receptors and sensors, and integrated via signaling within the cell and between cells. The withdrawal of such trophic support leads to a form of cellular suicide.

Contents

Various dependence receptors are involved in a range of biological events: developmental cell death (naturally occurring cell death), trophic factor withdrawal-induced cell death, the spontaneous regression characteristic of type IV-S neuroblastoma, neurodegenerative cell death, inhibition of new tumor cells (tumorigenesis) and metastasis, and therapeutic antibody-mediated tumor cell death, as well as programmed cell death in other instances. Since these receptors may support either cell death or cell survival, they initiate a new type of tumor suppressor, a conditional tumor suppressor. [3] In addition, events such as cellular atrophy and process retraction may also be mediated by dependence receptors, although this has not been as well documented as the induction of programmed cell death.

Receptors

The following is the list of known dependence receptors:

Background

Cells depend for their survival on stimulation that is mediated by various receptors and sensors. For any required stimulus, its withdrawal leads to a form of cellular suicide; that is, the cell plays an active role in its own demise. The term programmed cell death was first suggested by Lockshin & Williams [10] in 1964. Apoptosis, a form of programmed cell death, was first described by Kerr et al. in 1972, [11] although the earliest references to the morphological appearance of such cells may date back to the late 19th century.

Cells require different stimuli for survival, depending on their type and state of differentiation. For example, prostate epithelial cells require testosterone for survival, and the withdrawal of testosterone leads to apoptosis in these cells. How do cells recognize a lack of stimulus? While positive survival signals are clearly important, a complementary form of signal transduction is pro-apoptotic, and is activated or propagated by stimulus withdrawal or by the addition of an “anti-trophin.”

The dependence receptor notion was based on the observation that the effects of a number of receptors that function in both nervous system development and the production of tumors (especially metastasis) cannot be explained simply by a positive effect of signal transduction induced by ligand binding, but rather must also include cell death signaling in response to trophic withdrawal.

Positive survival signals involve classical signal transduction, initiated by interactions between ligands and receptors. Negative survival signals involve an alternative form of signal transduction that is initiated by the withdrawal of ligands from dependence receptors. This process is seen in developmental cell death, carcinogenesis (especially metastasis), neurodegeneration, and possibly non-lethal (sub-apoptotic) events such as neurite retraction and somal atrophy. Mechanistic studies of dependence receptors suggest that these receptors form complexes that activate and amplify caspase activity. In at least some cases, the caspase activation is via a pathway that is dependent on caspase-9 but not on mitochondria. Some of the downstream mediators have been identified, such as DAP kinase and the DRAL gene.

Dependence receptors display the common property that they mediate two different intracellular signals: in the presence of ligand, these receptors transduce a positive signal leading to survival, differentiation or migration; conversely, in the absence of ligand, the receptors initiate and/or amplify a signal for programmed cell death. Thus cells that express these proteins at sufficient concentrations manifest a state of dependence on their respective ligands. The signaling that mediates cell death induction upon ligand withdrawal is incompletely defined, but typically includes a required interaction with, and cleavage by, specific caspases. Mutation of the caspase site(s) in the receptor, of which there is typically one or two, prevents the trophic ligand withdrawal-induced programmed cell death.

Complex formation appears to be a function of ligand-receptor interaction, and dependence receptors appear to exist in at least two conformational states. Complex formation in the absence of ligand leads to caspase activation by a mechanism that is usually dependent on caspase cleavage of the receptor itself, releasing pro-apoptotic peptides. Thus these receptors may serve in caspase amplification, and in so doing create cellular states of dependence on their respective ligands. These states of dependence are not absolute, since they can be blocked downstream in some cases by the expression of anti-apoptotic genes such as Bcl-2 or P35. However, they result in a shift toward an increased likelihood of a cell's undergoing apoptosis.

Research

Research has highlighted the role of the dependence receptor UNC5D in the phenomenon of spontaneous regression of type IV-S neuroblastoma. [12] TrkA and TrkC have been shown to function as dependence receptors, [8] [7] with TrkC mediating both neural cell death and tumorigenesis. [13] In addition, although dependence receptors have been described as mediating programmed cell death in the absence of binding of trophic ligand, the possibility that a similar effect might be achieved by the binding of a physiological anti-trophin has been raised, and it has been suggested that the Alzheimer's disease-associated peptide, Aβ, may play such a role. [14]

Related Research Articles

<span class="mw-page-title-main">Apoptosis</span> Programmed cell death in multicellular organisms

Apoptosis is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses between 50 and 70 billion cells each day due to apoptosis. For an average human child between eight and fourteen years old, each day the approximate lost is 20 to 30 billion cells.

<span class="mw-page-title-main">Caspase</span> Family of cysteine proteases

Caspases are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with paracrine signaling, intracrine signaling, or classical endocrine signaling.

<span class="mw-page-title-main">Neurotrophin</span>

Neurotrophins are a family of proteins that induce the survival, development, and function of neurons.

<span class="mw-page-title-main">Fas ligand</span> Protein-coding gene in the species Homo sapiens

Fas ligand is a type-II transmembrane protein expressed on cytotoxic T lymphocytes and natural killer (NK) cells. Its binding with Fas receptor (FasR) induces programmed cell death in the FasR-carrying target cell. Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer.

<span class="mw-page-title-main">Nerve growth factor</span> Mammalian protein found in Homo sapiens

Nerve growth factor (NGF) is a neurotrophic factor and neuropeptide primarily involved in the regulation of growth, maintenance, proliferation, and survival of certain target neurons. It is perhaps the prototypical growth factor, in that it was one of the first to be described. Since it was first isolated by Nobel Laureates Rita Levi-Montalcini and Stanley Cohen in 1956, numerous biological processes involving NGF have been identified, two of them being the survival of pancreatic beta cells and the regulation of the immune system.

<span class="mw-page-title-main">Low-affinity nerve growth factor receptor</span> Human protein-coding gene

The p75 neurotrophin receptor (p75NTR) was first identified in 1973 as the low-affinity nerve growth factor receptor (LNGFR) before discovery that p75NTR bound other neurotrophins equally well as nerve growth factor. p75NTR is a neurotrophic factor receptor. Neurotrophic factor receptors bind Neurotrophins including Nerve growth factor, Neurotrophin-3, Brain-derived neurotrophic factor, and Neurotrophin-4. All neurotrophins bind to p75NTR. This also includes the immature pro-neurotrophin forms. Neurotrophic factor receptors, including p75NTR, are responsible for ensuring a proper density to target ratio of developing neurons, refining broader maps in development into precise connections. p75NTR is involved in pathways that promote neuronal survival and neuronal death.

<span class="mw-page-title-main">Tropomyosin receptor kinase C</span> Protein-coding gene in the species Homo sapiens

Tropomyosin receptor kinase C (TrkC), also known as NT-3 growth factor receptor, neurotrophic tyrosine kinase receptor type 3, or TrkC tyrosine kinase is a protein that in humans is encoded by the NTRK3 gene.

<span class="mw-page-title-main">Netrin receptor DCC</span> Protein-coding gene in the species Homo sapiens

Netrin receptor DCC, also known as DCC, or colorectal cancer suppressor is a protein which in humans is encoded by the DCC gene. DCC has long been implicated in colorectal cancer and its previous name was Deleted in colorectal carcinoma. Netrin receptor DCC is a single transmembrane receptor.

<span class="mw-page-title-main">Fas receptor</span> Protein found in humans

The Fas receptor, also known as Fas, FasR, apoptosis antigen 1, cluster of differentiation 95 (CD95) or tumor necrosis factor receptor superfamily member 6 (TNFRSF6), is a protein that in humans is encoded by the FAS gene. Fas was first identified using a monoclonal antibody generated by immunizing mice with the FS-7 cell line. Thus, the name Fas is derived from FS-7-associated surface antigen.

<span class="mw-page-title-main">Death-inducing signaling complex</span>

The death-inducing signaling complex or DISC is a multi-protein complex formed by members of the death receptor family of apoptosis-inducing cellular receptors. A typical example is FasR, which forms the DISC upon trimerization as a result of its ligand (FasL) binding. The DISC is composed of the death receptor, FADD, and caspase 8. It transduces a downstream signal cascade resulting in apoptosis.

<span class="mw-page-title-main">BH3 interacting-domain death agonist</span> Protein-coding gene in the species Homo sapiens

The BH3 interacting-domain death agonist, or BID, gene is a pro-apoptotic member of the Bcl-2 protein family. Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains, and can form hetero- or homodimers. Bcl-2 proteins act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities.

<span class="mw-page-title-main">Caspase 8</span> Protein-coding gene in the species Homo sapiens

Caspase-8 is a caspase protein, encoded by the CASP8 gene. It most likely acts upon caspase-3. CASP8 orthologs have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also present in birds.

Trk receptors are a family of tyrosine kinases that regulates synaptic strength and plasticity in the mammalian nervous system. Trk receptors affect neuronal survival and differentiation through several signaling cascades. However, the activation of these receptors also has significant effects on functional properties of neurons.

<span class="mw-page-title-main">RIPK1</span> Enzyme found in humans

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions in a variety of cellular pathways related to both cell survival and death. In terms of cell death, RIPK1 plays a role in apoptosis and necroptosis. Some of the cell survival pathways RIPK1 participates in include NF-κB, Akt, and JNK.

<span class="mw-page-title-main">Death receptor 6</span> Protein found in humans

Death receptor 6 (DR6), also known as tumor necrosis factor receptor superfamily member 21 (TNFRSF21), is a cell surface receptor of the tumor necrosis factor receptor superfamily which activates the JNK and NF-κB pathways. It is mostly expressed in the thymus, spleen and white blood cells. The Gene for DR6 is 78,450 bases long and is found on the 6th chromosome. This is transcribed into a 655 amino acid chain weighing 71.8 kDa. Post transcriptional modifications of this protein include glycosylation on the asparagines at the 82, 141, 252, 257, 278, and 289 amino acid locations.

Neurotrophic factor receptors or neurotrophin receptors are a group of growth factor receptors which specifically bind to neurotrophins.

<span class="mw-page-title-main">Necroptosis</span> Programmed form of necrosis, or inflammatory cell death

Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. The discovery of necroptosis showed that cells can execute necrosis in a programmed fashion and that apoptosis is not always the preferred form of cell death. Furthermore, the immunogenic nature of necroptosis favors its participation in certain circumstances, such as aiding in defence against pathogens by the immune system. Necroptosis is well defined as a viral defense mechanism, allowing the cell to undergo "cellular suicide" in a caspase-independent fashion in the presence of viral caspase inhibitors to restrict virus replication. In addition to being a response to disease, necroptosis has also been characterized as a component of inflammatory diseases such as Crohn's disease, pancreatitis, and myocardial infarction.

<span class="mw-page-title-main">Paraptosis</span> Type of programmed cell death distinct from apoptosis and necrosis

Paraptosis is a type of programmed cell death, morphologically distinct from apoptosis and necrosis. The defining features of paraptosis are cytoplasmic vacuolation, independent of caspase activation and inhibition, and lack of apoptotic morphology. Paraptosis lacks several of the hallmark characteristics of apoptosis, such as membrane blebbing, chromatin condensation, and nuclear fragmentation. Like apoptosis and other types of programmed cell death, the cell is involved in causing its own death, and gene expression is required. This is in contrast to necrosis, which is non-programmed cell death that results from injury to the cell.

Patrick Mehlen, is a French biologist and research director at the Centre national de recherche scientifique (CNRS) at the Centre Léon-Bérard, a cancer research centre in Lyon.

References

  1. ↑ Bredesen DE, Mehlen P, Rabizadeh S (April 2004). "Apoptosis and Dependence Receptors: A Molecular Basis for Cellular Addiction". Physiological Reviews. 84 (2): 411–430. doi:10.1152/physrev.00027.2003. PMID   15044679.
  2. ↑ Mehlen, Patrick (December 2010). "Dependence Receptors: The Trophic Theory Revisited". Science Signaling. 3 (151): pe47. doi:10.1126/scisignal.3151pe47. PMID   21139137. S2CID   206673626.
  3. ↑ Mazelin L; et al. (September 2004). "Netrin-1 controls colorectal tumorigenesis by regulating apoptosis". Nature. 431 (7004): 80–84. Bibcode:2004Natur.431...80M. doi:10.1038/nature02788. PMID   15343335. S2CID   4417992.
  4. ↑ Lin, Shuheng; Negulescu, Ana; Bulusu, Sirisha; Gibert, Benjamin; Delcros, Jean-Guy; Ducarouge, Benjamin; Rama, Nicolas; Gadot, Nicolas; Treilleux, Isabelle (2017-07-18). "Non-canonical NOTCH3 signalling limits tumour angiogenesis". Nature Communications. 8: ncomms16074. Bibcode:2017NatCo...816074L. doi:10.1038/ncomms16074. PMC   5520050 . PMID   28719575.
  5. ↑ Causeret, F.; Sumia, I.; Pierani, A. (February 2016). "Kremen1 and Dickkopf1 control cell survival in a Wnt-independent manner". Cell Death & Differentiation. 23 (2): 323–332. doi:10.1038/cdd.2015.100. ISSN   1350-9047. PMC   4716294 . PMID   26206087.
  6. ↑ Rabizadeh S; et al. (July 1993). "Induction of apoptosis by the low-affinity NGF receptor". Science. 261 (5119): 345–348. Bibcode:1993Sci...261..345R. doi:10.1126/science.8332899. PMID   8332899.
  7. 1 2 Nikoletopoulou V; et al. (September 2010). "Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not". Nature. 467 (7311): 59–63. Bibcode:2010Natur.467...59N. doi:10.1038/nature09336. hdl: 10261/27437 . PMID   20811452. S2CID   205222117.
  8. 1 2 Tauszig-Delamasure S; et al. (August 2007). "The TrkC receptor induces apoptosis when the dependence receptor notion meets the neurotrophin paradigm". PNAS. 104 (33): 13361–13366. Bibcode:2007PNAS..10413361T. doi: 10.1073/pnas.0701243104 . PMC   1948910 . PMID   17686986.
  9. ↑ Mourali, Jaouhar; Bénard, Alan; Lourenço, Filipe Calheiros; Monnet, Céline; Greenland, Catherine; Moog-Lutz, Christel; Racaud-Sultan, Claire; Gonzalez-Dunia, Daniel; Vigny, Marc (2006-08-15). "Anaplastic Lymphoma Kinase Is a Dependence Receptor Whose Proapoptotic Functions Are Activated by Caspase Cleavage". Molecular and Cellular Biology. 26 (16): 6209–6222. doi:10.1128/mcb.01515-05. ISSN   0270-7306. PMC   1592804 . PMID   16880530.
  10. ↑ Lockshin RA, Williams CM (1964). "Programmed cell death—II. Endocrine potentiation of the breakdown of the intersegmental muscles of silkmoths". Journal of Insect Physiology. 10 (4): 643–649. doi:10.1016/0022-1910(64)90034-4.
  11. ↑ Kerr JF, Wyllie AH, Currie AR (August 1972). "Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics". Br. J. Cancer. 26 (4): 239–57. doi:10.1038/bjc.1972.33. PMC   2008650 . PMID   4561027.
  12. ↑ Zhu Y; et al. (June 2013). "Dependence receptor UNC5D mediates nerve growth factor depletion–induced neuroblastoma regression". The Journal of Clinical Investigation. 123 (7): 2935–2947. doi:10.1172/JCI65988. PMC   3696554 . PMID   23778138.
  13. ↑ Genevois AL; et al. (February 2013). "Dependence receptor TrkC is a putative colon cancer tumor suppressor". PNAS. 110 (8): 3017–3022. doi: 10.1073/pnas.1212333110 . PMC   3581924 . PMID   23341610.
  14. ↑ Bredesen DE (June 2009). "Neurodegeneration in Alzheimer's disease:caspases and synaptic element interdependence". Molecular Neurodegeneration. 4 (27): 27. doi: 10.1186/1750-1326-4-27 . PMC   2709109 . PMID   19558683.
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