Regulated Segregation of Kinase Dyrk1A during Asymmetric Neural Stem Cell Division Is Critical for EGFR-Mediated Biased Signaling

Ferrón, Sacri R.; Pozo, Natividad; Laguna, Ariadna; Aranda, Sergi; Porlan, Eva; Moreno, M. Moreno; Fillat, Cristina; Luna, Susana de la; Sánchez, Pilar Fernández; Arbonés, María L.; Fariñas, Isabel

doi:10.1016/j.stem.2010.06.021

Cited by 71 publications

(62 citation statements)

References 50 publications

(80 reference statements)

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“…These data suggest that MNB/DYRK1A may act as a cell determinant of neurogenesis. Accordingly, neural stem cells from Dyrk1a +/-mice exhibit defects in self-renewal (Ferrón et al, 2010). We have shown here that subsequent to the mentioned expression in preneurogenic NPs, Mnb/Dyrk1a is again transiently expressed in prospective neurons.…”

Section: Kip1mentioning

confidence: 62%

Transient expression of Mnb/Dyrk1a couples cell cycle exit and differentiation of neuronal precursors by inducing p27KIP1 expression and suppressing NOTCH signaling

Hämmerle¹,

Ulin²,

Guimerà³

et al. 2011

Development

119

101

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SUMMARYThe decision of a neural precursor to stop dividing and begin its terminal differentiation at the correct place, and at the right time, is a crucial step in the generation of cell diversity in the nervous system. Here, we show that the Down's syndrome candidate gene (Mnb/Dyrk1a) is transiently expressed in prospective neurons of vertebrate CNS neuroepithelia. The gain of function (GoF) of Mnb/Dyrk1a induced proliferation arrest. Conversely, its loss of function (LoF) caused over proliferation and cell death. We found that MNB/DYRK1A is both necessary and sufficient to upregulate, at transcriptional level, the expression of the cyclin-dependent kinase inhibitor p27 KIP1 in the embryonic chick spinal cord and mouse telencephalon, supporting a regulatory role for MNB/DYRK1A in cell cycle exit of vertebrate CNS neurons. All these actions required the kinase activity of MNB/DYRK1A. We also observed that MNB/DYRK1A is co-expressed with the NOTCH ligand Delta1 in single neuronal precursors. Furthermore, we found that MNB/DYRK1A suppressed NOTCH signaling, counteracted the pro-proliferative action of the NOTCH intracellular domain (NICD), stimulated Delta1 expression and was required for the neuronal differentiation induced by the decrease in NOTCH signaling. Nevertheless, although Mnb/Dyrk1a GoF led to extensive withdrawal of neuronal precursors from the cell cycle, it was insufficient to elicit their differentiation. Remarkably, a transient (ON/OFF) Mnb/Dyrk1a GoF efficiently induced neuronal differentiation. We propose that the transient expression of MNB/DYRK1A in neuronal precursors acts as a binary switch, coupling the end of proliferation and the initiation of neuronal differentiation by upregulating p27KIP1 expression and suppressing NOTCH signaling.

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Section: Kip1mentioning

confidence: 62%

Transient expression of Mnb/Dyrk1a couples cell cycle exit and differentiation of neuronal precursors by inducing p27KIP1 expression and suppressing NOTCH signaling

Hämmerle¹,

Ulin²,

Guimerà³

et al. 2011

Development

119

101

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“…Dyrk1A heterozygous SVZ contained fewer EGFR-positive cells, leading to diminished NSC activation in response to EGF. Our data indicate that DYRK1A prevents endocytotic degradation of EGFR through the phosphorylation of the EGFR-signaling modulator Sprouty2 (SPRY2) (28).…”

Section: Introductionmentioning

confidence: 74%

“…The absence of an effect in LN18 cells could reflect the low levels of EGFR surface expression by this cell line (3.4 ± 0.2 % of positive cells) when compared with the sensitive cell lines. Furthermore, reducing DYRK1A did not influence BrdU incorporation in U87 cells (Supplemental Figure 1B), suggesting that it specifically modulates the self-renewal capacity of GBM cells as in normal NSCs (28).…”

Section: Dyrk1a Modulates Egfr Protein Levels and The Self-renewal Ofmentioning

confidence: 96%

Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth

Pozo

Zahonero²,

Fernández³

et al. 2013

J. Clin. Invest.

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126

149

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Glioblastomas (GBMs) are very aggressive tumors that are resistant to conventional chemo-and radiotherapy. New molecular therapeutic strategies are required to effectively eliminate the subpopulation of GBM tumorinitiating cells that are responsible for relapse. Since EGFR is altered in 50% of GBMs, it represents one of the most promising targets; however, EGFR kinase inhibitors have produced poor results in clinical assays, with no clear explanation for the observed resistance. We uncovered a fundamental role for the dual-specificity tyrosine phosphorylation-regulated kinase, DYRK1A, in regulating EGFR in GBMs. We found that DYRK1A was highly expressed in these tumors and that its expression was correlated with that of EGFR. Moreover, DYRK1A inhibition promoted EGFR degradation in primary GBM cell lines and neural progenitor cells, sharply reducing the self-renewal capacity of normal and tumorigenic cells. Most importantly, our data suggest that a subset of GBMs depends on high surface EGFR levels, as DYRK1A inhibition compromised their survival and produced a profound decrease in tumor burden. We propose that the recovery of EGFR stability is a key oncogenic event in a large proportion of gliomas and that pharmacological inhibition of DYRK1A could represent a promising therapeutic intervention for EGFR-dependent GBMs.

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“…Sorting of growth factor and signaling receptors, including EGFR intracellular trafficking, have been shown to be essential processes for the regulation of stem cell self-renewal (15). Other mechanisms, such as how EGFR signaling can be maintained in stem cells with continuous endocytic recycling, however, have not been evaluated.…”

mentioning

confidence: 99%

Interaction of ganglioside GD3 with an EGF receptor sustains the self-renewal ability of mouse neural stem cells in vitro

Wang

2013

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

100

102

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Mounting evidence supports the notion that gangliosides serve regulatory roles in neurogenesis; little is known, however, about how these glycosphingolipids function in neural stem cell (NSC) fate determination. We previously demonstrated that ganglioside GD3 is a major species in embryonic mouse brain: more than 80% of the NSCs obtained by the neurosphere method express GD3. To investigate the functional role of GD3 in neurogenesis, we compared the properties of NSCs from GD3-synthase knockout (GD3S-KO) mice with those from their wild-type littermates. NSCs from GD3S-KO mice showed decreased self-renewal ability compared with those from the wild-type animals, and that decreased ability was accompanied by reduced expression of EGF receptor (EGFR) and an increased degradation rate of EGFR and EGF-induced ERK signaling. We also showed that EGFR switched from the low-density lipid raft fractions in wild-type NSCs to the high-density layers in the GD3S-KO NSCs. Immunochemical staining revealed colocalization of EGFR and GD3, and EGFR could be immunoprecipitated from the NSC lysate with an anti-GD3 antibody from the wild-type, but not from the GD3S-KO, mice. Tracking the localization of endocytosed EGFR with endocytosis pathway markers indicated that more EGFR in GD3S-KO NSCs translocated through the endosomal−lysosomal degradative pathway, rather than through the recycling pathway. Those findings support the idea that GD3 interacts with EGFR in the NSCs and that the interaction is responsible for sustaining the expression of EGFR and its downstream signaling to maintain the selfrenewal capability of NSCs.G angliosides are ubiquitously expressed in all vertebrate cells and are particularly abundant in the nervous system (1). In early mammalian embryonic brain, the pattern of ganglioside expression is limited to simple gangliosides, predominantly GM3 (NeuAcα2-3Galβ1-4Glcβ1-1′Cer) and GD3 (NeuAcα2-8NeuAcα2-3Galβ1-4Glcβ1-1′Cer). In later developmental stages, however, more complex gangliosides prevail, particularly GM1 (Galβ1-3GalNAcβ1-4(NeuAcα2-3)Galβ1-4Glcβ1-1′Cer), GD1a (NeuAcα2-3Galβ1-3GalNAcβ1-4(NeuAcα2-3)Galβ1-4Glcβ1-1′ Cer), GD1b (Galβ1-3GalNAcβ1-4(NeuAcα2-8NeuAcα2-3) Galβ1-4Glcβ1-1′Cer), and GT1b (NeuAcα2-3Galβ1-3GalNAcβ1-4 (NeuAcα2-8NeuAcα2-3)Galβ1-4Glcβ1-1′Cer) (2, 3). Because of the spatiotemporal expression patterns, gangliosides abundant in embryonic brain, such as GD3 and the c-series ganglioside antigen marker A2B5, have been considered to be useful stage-specific markers of early brain development (4, 5). Mounting evidence supports the notion that gangliosides serve regulatory roles in neurogenesis through modulating processes, such as intercellular recognition, interaction, adhesion, reception, and/ or signaling (6-9). Little is known, however, about how glycosphingolipids (GSLs) function in neural stem cell (NSC) fate determination. Investigation of the biological significance of gangliosides has also been greatly facilitated by the analysis of genetically engineered mice deficient in one or more gangl...

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Regulated Segregation of Kinase Dyrk1A during Asymmetric Neural Stem Cell Division Is Critical for EGFR-Mediated Biased Signaling

Cited by 71 publications

References 50 publications

Transient expression of Mnb/Dyrk1a couples cell cycle exit and differentiation of neuronal precursors by inducing p27KIP1 expression and suppressing NOTCH signaling

Transient expression of Mnb/Dyrk1a couples cell cycle exit and differentiation of neuronal precursors by inducing p27KIP1 expression and suppressing NOTCH signaling

Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth

Interaction of ganglioside GD3 with an EGF receptor sustains the self-renewal ability of mouse neural stem cells in vitro

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