The dependence receptor Ret induces apoptosis in somatotrophs through a Pit-1/p53 pathway, preventing tumor growth

Cañibano, Carmen; Rodriguez, Noela L; Sáez, Carmen; Tovar, Sulay; García-Lavandeira, Montserrat; Borrello, Maria Grazia; Vidal, Anxo; Costantini, Frank; Japón, Miguel Á.; Diéguez, Carlos; Álvarez, Clara V.

doi:10.1038/sj.emboj.7601636

Cited by 72 publications

(121 citation statements)

References 53 publications

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“…The observation that RET is involved in both cancer progression and nervous system development, similar to previously identified DRs, led to the question as to whether it could also be one of them. It was then shown that, in different settings, expression of RET induced apoptosis in the absence, but not in the presence, of glial cell line-derived neurotrophic factor (Bordeaux et al, 2000;Canibano et al, 2007).…”

Section: Dependence Receptors: a Short Historymentioning

confidence: 99%

Dependence receptors: a new paradigm in cell signaling and cancer therapy

2010

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Dependence receptors (DRs) now form a family of more than a dozen membrane receptors that are not linked by 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 activate classic signaling pathways implicated in cell survival, migration and differentiation. In the absence of ligand, they do not stay inactive, rather they elicit an apoptotic signal. Thus, cells expressing this kind of receptor are dependent on the presence of ligand in the extracellular environment to survive. This review will recapitulate the increasing data regarding the molecular mechanisms associated with DRs, their potential implication during development, as well as their deregulation during tumorigenesis and, finally, their emergence as new possible therapeutic targets for cancer treatment.

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Section: Dependence Receptors: a Short Historymentioning

confidence: 99%

Dependence receptors: a new paradigm in cell signaling and cancer therapy

2010

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“…In contrast to its well-established role as an oncogene for several cancer types, RET has been recently proposed to play tumor suppressor roles in colorectal cancer (CRC) and pituitary adenoma [46,47]. Such tumor suppressor role might be functionally linked to a pro-apoptotic role exerted by RET by behaving as a "dependence" receptor [48].…”

Section: Ret As a Tumor Suppressormentioning

confidence: 99%

“…When stimulated by GDNF, it behaved as as an oncogene able to activate intracellular signaling and cell survival. Instead, in the absence of GDNF, RET behaved as a tumor suppressor; caspase-mediated RET processing induced Pit-1 expression, that, in turn, caused p19Arf and p53 upregulation and apoptosis [46,49].…”

Section: Ret As a Tumor Suppressormentioning

confidence: 99%

RET: A Multi-Faceted Gene in Human Cancer

2012

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“…This promotes RET cleavage, leading finally to p53 expression and apoptosis (Canibano et al, 2007). In the case of ErbB2, it has been shown that the fragment generated through the caspase-dependent cleavage contains a BH3-like domain involved in its mitochondrial localization and its association with the anti-apoptotic protein, Bcl-x L .…”

Section: Both Survival Receptors and Messengers Of Deathmentioning

confidence: 99%

Proteolytic cleavages give receptor tyrosine kinases the gift of ubiquity

et al. 2009

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Receptor tyrosine kinases (RTK) constitute a large family of membrane receptors which, in response to their respective ligand, transmit information into cells. RTK regulate multiple biological responses, and their deregulation is often associated with tumourigenesis. The intracellular signalling pathways initiated by full-length membrane RTK are studied extensively, but many RTK fragments showing unexpected cellular localization have been observed. These fragments are generated by proteolytic cleavages, catalyzed notably by caspases, membrane metalloproteases or g-secretase. Interestingly, these cleavages, in addition to regulating membrane receptor levels, generate active fragments that can regulate biological processes, such as transcription or the survival/apoptosis balance. Thus, proteolytic cleavages release RTK from the membrane and extend their functions. Furthermore, the RTK proteolysis are involved in regulating cell transformation, which highlights their potential as attractive targets for therapeutic strategies. Keywords: receptor tyrosine kinase; cleavages; caspase; metalloprotease; g-secretase; signalling RTK as a membrane mediator between the extracellular and intracellular compartmentsIn multicellular organisms, the dialogue between cells is crucial to harmonious development and, in adults, to tissue homeostasis. This dialogue operates notably through soluble cytokines and their cognate membrane receptors. Cytokines secreted by cells into the extracellular environment can bind with high affinity to the extracellular domains of their respective specific membrane receptors expressed on the surface of target cells. Ligand binding triggers activation of the receptor, which transmits the information from the extracellular to the intracellular compartment. Receptor tyrosine kinases (RTK) constitute a large family of information-transmitting membrane receptors. The variability of their extracellular regions results in a wide specificity range as regards cytokine ligands. Inversely, their intracellular regions possess a conserved tyrosine kinase domain, involved in message transmission (Hubbard and Till, 2000). Ligand-activated RTK can initiate multiple biological responses, including proliferation, cell motility, survival and differentiation.Receptor tyrosine kinases are activated through dimerization and trans-autophosphorylation of tyrosine residues. The intracellular region of an RTK then becomes a signalling platform that can recruit numerous cytoplasmic proteins through phosphorylated tyrosine residues. In turn, these signalling proteins activate signalling pathways commonly organized in a cascade, which will propagate the information inside the cell (Schlessinger, 2000). The signalling cascades are often interconnected and are able to activate or downregulate each other (Amit et al., 2007). Therefore, the entire intracellular signalling mechanism is viewed as a network rather than as a superposition of multiple linear pathways.In keeping with the involvement of RTK in controlling a wide range of bi...

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The dependence receptor Ret induces apoptosis in somatotrophs through a Pit-1/p53 pathway, preventing tumor growth

Cited by 72 publications

References 53 publications

Dependence receptors: a new paradigm in cell signaling and cancer therapy

Dependence receptors: a new paradigm in cell signaling and cancer therapy

RET: A Multi-Faceted Gene in Human Cancer

Proteolytic cleavages give receptor tyrosine kinases the gift of ubiquity

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