RasGAP Shields Akt from Deactivating Phosphatases in Fibroblast Growth Factor Signaling but Loses This Ability Once Cleaved by Caspase-3

Cailliau, Kátia; Lescuyer, Arlette; Burnol, Anne-Françoise; Cuesta-Marbán, Álvaro; Widmann, Christian; Browaeys-Poly, Edith

doi:10.1074/jbc.m115.644633

Cited by 4 publications

(6 citation statements)

References 69 publications

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“…Similar results were obtained using MEF cells derived from SCP1-WT and -KO littermates under the insulin treatment ( Figure 5F ). Phosphatase PHLPP has been implicated in cleaving pS473 from AKT ( Cailliau et al, 2015 ; Qiao et al, 2007 ). We found that SCP1 or PHLPP depletion could promote AKT phosphorylation at Ser473.…”

Section: Resultsmentioning

confidence: 99%

Palmitoylated SCP1 is targeted to the plasma membrane and negatively regulates angiogenesis

Liao

Wang

et al. 2017

eLife

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SCP1 as a nuclear transcriptional regulator acts globally to silence neuronal genes and to affect the dephosphorylation of RNA Pol ll. However, we report the first finding and description of SCP1 as a plasma membrane-localized protein in various cancer cells using EGFP- or other epitope-fused SCP1. Membrane-located SCP1 dephosphorylates AKT at serine 473, leading to the abolishment of serine 473 phosphorylation that results in suppressed angiogenesis and a decreased risk of tumorigenesis. Consistently, we observed increased AKT phosphorylation and angiogenesis followed by enhanced tumorigenesis in Ctdsp1 (which encodes SCP1) gene - knockout mice. Importantly, we discovered that the membrane localization of SCP1 is crucial for impeding angiogenesis and tumor growth, and this localization depends on palmitoylation of a conserved cysteine motif within its NH2 terminus. Thus, our study discovers a novel mechanism underlying SCP1 shuttling between the plasma membrane and nucleus, which constitutes a unique pathway in transducing AKT signaling that is closely linked to angiogenesis and tumorigenesis.DOI: http://dx.doi.org/10.7554/eLife.22058.001

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Section: Resultsmentioning

confidence: 99%

Palmitoylated SCP1 is targeted to the plasma membrane and negatively regulates angiogenesis

Liao

Wang

et al. 2017

eLife

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“…In contrast, fragment N contributes to cell protection through the Ras/PI3K/Akt/mTOR pathway. Data reveal that fragment N could increase insulin-induced ERK2 phosphorylation and G 2 /M transition through interacting with RhoGAP via the SH2 domain to promote cell growth [ 130 ].…”

Section: The Interplay Between Mtor Signaling and The Caspase Famimentioning

confidence: 99%

“…Importantly, it directly suppresses the phosphorylation of Akt Ser 473, further attenuating the phosphorylation of the Thr 308 and leading to a decrease of Akt activity. Finally, it serves as an apoptosis inducer [ 130 ].…”

Section: The Interplay Between Mtor Signaling and The Caspase Famimentioning

confidence: 99%

“…Further research demonstrates that the sole segment of SH2–SH3–SH2 can also block the ERK phosphorylation, the G 2 /M transition and the phosphorylation of Akt Ser 473, indicating that the SH2–SH3–SH2 fragment of fragment N2 is the key function structure. In fact, the SH2-SH3-SH2 fragment of fragment N2 interacts with the growth factor receptor, wrecking the existing combination of the Akt/FGFR/RasGAP complex [ 130 ]. The SH3 domain alone has no effect on Akt phosphorylation.…”

Section: The Interplay Between Mtor Signaling and The Caspase Famimentioning

confidence: 99%

“…A hypothesis states that the interaction between the SH3 domain and the polyproline-rich domain of fragment N affects the conformation of the SH2–SH3–SH2 domain and binding with receptor complex. Disrupting the interaction of SH3 domain and the polyproline-rich domain with a mutation of SH3 domain leads to fragment N combining with Akt and the receptor to prevent binding with full-length RasGAP [ 130 ]. This result leads to the inhibition of Akt Ser 473 phosphorylation.…”

Section: The Interplay Between Mtor Signaling and The Caspase Famimentioning

confidence: 99%

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Crosstalk of the Caspase Family and Mammalian Target of Rapamycin Signaling

Yan

Xie

et al. 2021

IJMS

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Cell can integrate the caspase family and mammalian target of rapamycin (mTOR) signaling in response to cellular stress triggered by environment. It is necessary here to elucidate the direct response and interaction mechanism between the two signaling pathways in regulating cell survival and determining cell fate under cellular stress. Members of the caspase family are crucial regulators of inflammation, endoplasmic reticulum stress response and apoptosis. mTOR signaling is known to mediate cell growth, nutrition and metabolism. For instance, over-nutrition can cause the hyperactivation of mTOR signaling, which is associated with diabetes. Nutrition deprivation can inhibit mTOR signaling via SH3 domain-binding protein 4. It is striking that Ras GTPase-activating protein 1 is found to mediate cell survival in a caspase-dependent manner against increasing cellular stress, which describes a new model of apoptosis. The components of mTOR signaling-raptor can be cleaved by caspases to control cell growth. In addition, mTOR is identified to coordinate the defense process of the immune system by suppressing the vitality of caspase-1 or regulating other interferon regulatory factors. The present review discusses the roles of the caspase family or mTOR pathway against cellular stress and generalizes their interplay mechanism in cell fate determination.

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Efficient regulation of branching morphogenesis via fibroblast growth factor receptor 2c in early-stage embryonic mouse salivary glands

et al. 2016

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RasGAP Shields Akt from Deactivating Phosphatases in Fibroblast Growth Factor Signaling but Loses This Ability Once Cleaved by Caspase-3

Cited by 4 publications

References 69 publications

Palmitoylated SCP1 is targeted to the plasma membrane and negatively regulates angiogenesis

Palmitoylated SCP1 is targeted to the plasma membrane and negatively regulates angiogenesis

Crosstalk of the Caspase Family and Mammalian Target of Rapamycin Signaling

Efficient regulation of branching morphogenesis via fibroblast growth factor receptor 2c in early-stage embryonic mouse salivary glands

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