ASPP2 Binds Par-3 and Controls the Polarity and Proliferation of Neural Progenitors during CNS Development

Sottocornola, Roberta; Royer, Christophe; Vives, Virginie; Tordella, Luca; Zhong, Shan; Wang, Yihua; Ratnayaka, Indrika; Shipman, Mark; Cheung, Ankie Tan; Gaston‐Massuet, Carles; Ferretti, Patrizia; Molnár, Zoltán; Lü, Xin

doi:10.1016/j.devcel.2010.06.003

Cited by 110 publications

(137 citation statements)

References 29 publications

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“…As a result, ASPP2 inhibits RAS-induced autophagy by preventing the formation of the ATG16/ATG5/ATG12 trimeric complex. In epithelial cells, ASPP2 binds and colocalizes with Par3 at the tight/adherens junctions in vitro and in vivo (18,20). Here, we show that on RAS activation, ASPP2 translocates from cell/cell junctions to the cytoplasm.…”

Section: Discussionmentioning

confidence: 72%

“…To identify the region of ASPP2 that mediates RAS-induced senescence, two ASPP2 mutants were generated: ASPP2(1-360) and ASPP2(123-1,128). ASPP2(1-360) does not bind p53 but contains a ubiquitin-like fold similar to ATG12 or LC3 and binds Par3 (18,20). ASPP2(123-1,128) binds p53 and Par3 but lacks the ubiquitin-like fold and represents a naturally occurring ASPP2 splice variant (21) (Fig.…”

Section: N-terminal Aspp2 Mediates Ras-induced Senescence and Inhibitsmentioning

confidence: 99%

“…Nonetheless, recent studies showed that ASPP2 is able to suppress cell proliferation through p53-independent pathways. By binding to Par3, ASPP2 is able to maintain the integrity of cell polarity and suppress excessive growth of neural progenitors (18). The ability of ASPP2 to suppress cell proliferation independent of p53 is conserved because dASPP inhibits cell proliferation in Drosophila independent of p53 (19).…”

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Autophagic activity dictates the cellular response to oncogenic RAS

Wang

Lapi

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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RAS is frequently mutated in human cancers and has opposing effects on autophagy and tumorigenesis. Identifying determinants of the cellular responses to RAS is therefore vital in cancer research. Here, we show that autophagic activity dictates the cellular response to oncogenic RAS. N-terminal Apoptosis-stimulating of p53 protein 2 (ASPP2) mediates RAS-induced senescence and inhibits autophagy. Oncogenic RAS-expressing ASPP2 (Δ3/Δ3) mouse embryonic fibroblasts that escape senescence express a high level of ATG5/ATG12. Consistent with the notion that autophagy levels control the cellular response to oncogenic RAS, overexpressing ATG5, but not autophagy-deficient ATG5 mutant K130R, bypasses RAS-induced senescence, whereas ATG5 or ATG3 deficiency predisposes to it. Mechanistically, ASPP2 inhibits RAS-induced autophagy by competing with ATG16 to bind ATG5/ATG12 and preventing ATG16/ATG5/ATG12 formation. Hence, ASPP2 modulates oncogenic RAS-induced autophagic activity to dictate the cellular response to RAS: to proliferate or senesce.A ctive mutations of RAS, one of the first oncogenes identified, occur in about 20% of human tumors (1). Oncogenic RAS can transform cells and promote tumorigenesis, although it can also induce senescence and suppress tumor growth (2). Senescent cells are arrested and incapable of responding to mitogens, although they are viable and metabolically active. Senescence is characterized by dramatic cellular remodelling, which is energetically demanding. Autophagy, a genetically regulated process responsible for the turnover of cellular proteins and damaged or superfluous organelles, is a stress response involved in energy homeostasis (3). It was shown that autophagy is a critical mediator of oncogenic RAS-induced senescence, suggesting a negative role of autophagy in tumorigenesis (4). In contrast, a number of recent studies showed that active RAS requires autophagy to maintain its oncogenic function in tumorigenesis, arguing for a positive role of autophagy in tumorigenesis (5-8). The underlying reason for the conflicting observations remains unclear.RAS activation inhibits autophagy by activating the PI3K/ AKT/mammalian target of rapamycin (mTOR) pathway (9), and rapamycin, an mTOR inhibitor, is a potent inducer of autophagy. RAS also inhibits autophagy by reducing Beclin-1 expression in intestinal epithelial cells, an important mediator of autophagy (10). However, RAS was reported to induce autophagy by increasing the expression of key components of the autophagy machinery, such as ATG5 (11) and Beclin-1 (12). These reports suggest that RAS signaling performs a finely regulated balancing act to control autophagy. Identification of switching molecules that determine the cellular responses to RAS is thus needed urgently.The tumor suppressor p53 is one of the most well-established pathways by which RAS mediates cellular senescence. A recent study also showed that p53 is able to regulate autophagic activity by inducing the expression of LC3 (13). However, it remains unknown whether the abilit...

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Section: Discussionmentioning

confidence: 72%

Section: N-terminal Aspp2 Mediates Ras-induced Senescence and Inhibitsmentioning

confidence: 99%

mentioning

confidence: 99%

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Autophagic activity dictates the cellular response to oncogenic RAS

Wang

Lapi

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Mouse hearts at various developmental stages were dissected and processed for histological examination as previously described (16). For immunofluorescence staining, tissues sections were incubated overnight at 4°C with mouse monoclonal antibodies against iASPP (LX128.5) and desmoplakin I and II (Progen Scientific Ltd) or with rabbit polyclonal antibodies against desmin, γ-catenin, N-cadherin, and connexin 43 (Abcam), followed by either biotinylated or Alexa Fluor (1:400; Molecular Probes)-conjugated secondary antibody for 30 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…Interestingly, ASPP2 recently was identified as an important regulator of cell polarity and cell proliferation during the development of the central nervous system through its binding to Par3, thus maintaining the integrity of tight/adherens junctions. This function of ASPP2 is mediated by its N terminus independently of p53 (16,17).…”

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confidence: 99%

iASPP, a previously unidentified regulator of desmosomes, prevents arrhythmogenic right ventricular cardiomyopathy (ARVC)-induced sudden death

Notari

Sutendra

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Desmosomes are anchoring junctions that exist in cells that endure physical stress such as cardiac myocytes. The importance of desmosomes in maintaining the homeostasis of the myocardium is underscored by frequent mutations of desmosome components found in human patients and animal models. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a phenotype caused by mutations in desmosomal components in ∼50% of patients, however, the causes in the remaining 50% of patients still remain unknown. A deficiency of inhibitor of apoptosis-stimulating protein of p53 (iASPP), an evolutionarily conserved inhibitor of p53, caused by spontaneous mutation recently has been associated with a lethal autosomal recessive cardiomyopathy in Poll Hereford calves and Wa3 mice. However, the molecular mechanisms that mediate this putative function of iASPP are completely unknown. Here, we show that iASPP is expressed at intercalated discs in human and mouse postmitotic cardiomyocytes. iASPP interacts with desmoplakin and desmin in cardiomyocytes to maintain the integrity of desmosomes and intermediate filament networks in vitro and in vivo. iASPP deficiency specifically induces right ventricular dilatation in mouse embryos at embryonic day 16.5. iASPPdeficient mice with exon 8 deletion (Ppp1r13l Δ8/Δ8 ) die of sudden cardiac death, displaying features of ARVC. Intercalated discs in cardiomyocytes from four of six human ARVC cases show reduced or loss of iASPP. ARVC-derived desmoplakin mutants DSP-1-V30M and DSP-1-S299R exhibit weaker binding to iASPP. These data demonstrate that by interacting with desmoplakin and desmin, iASPP is an important regulator of desmosomal function both in vitro and in vivo. This newly identified property of iASPP may provide new molecular insight into the pathogenesis of ARVC.ARVC | sudden death | desmosome | iASPP | cell-cell junctions

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Neocortical Neurogenesis in Amniote Evolution

Fernández,

Borrell

2023

Neocortical Neurogenesis in Development and Evolution

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ASPP2 Binds Par-3 and Controls the Polarity and Proliferation of Neural Progenitors during CNS Development

Cited by 110 publications

References 29 publications

Autophagic activity dictates the cellular response to oncogenic RAS

Autophagic activity dictates the cellular response to oncogenic RAS

iASPP, a previously unidentified regulator of desmosomes, prevents arrhythmogenic right ventricular cardiomyopathy (ARVC)-induced sudden death

Neocortical Neurogenesis in Amniote Evolution

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