Simple differentiation method using FBS identifies DUSP6 as a marker for fine-tuning of FGF-ERK signaling activity in human pluripotent stem cells

Yoo, Dae Hoon; Im, Young Sam; Jo, Eun Hee; Kim, Bo Young; Jo, Hye‐Yeong; Park, Mi-Hyun; Koo, Soo Kyung; Kim, Yong-Ou

doi:10.1016/j.bbrc.2019.10.081

Cited by 3 publications

(5 citation statements)

References 34 publications

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“…SPROUTY interacts with GRB2 to regulate the activation of MAPK and PI3K–AKT downstream from FGFR phosphorylation [ 77 , 78 ] ( figure 3 ). Phosphatases like DUSP6 or SHP2 attenuate the FGFR/MAPK signalling axis during development, and their deregulation may lead to cancer formation [ 79 , 80 ]. Finally, the E3 ubiquitin ligase CBL induces the ubiquitylation of FGFR after receptor internalization and regulates the sorting of FGFR into the degradative pathway which results in signalling termination [ 81 ] ( figure 3 ).…”

Section: Fgfr Signalling In Health and Diseasementioning

confidence: 99%

Fibroblast growth factor receptor signalling dysregulation and targeting in breast cancer

Francavilla

O'Brien

2022

Open Biol.

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Fibroblast Growth Factor Receptor (FGFR) signalling plays a critical role in breast embryonal development, tissue homeostasis, tumorigenesis and metastasis. FGFR, its numerous FGF ligands and signalling partners are often dysregulated in breast cancer progression and are one of the causes of resistance to treatment in breast cancer. Furthermore, FGFR signalling on epithelial cells is affected by signals from the breast microenvironment, therefore increasing the possibility of breast developmental abnormalities or cancer progression. Increasing our understanding of the multi-layered roles of the complex family of FGFRs, their ligands FGFs and their regulatory partners may offer novel treatment strategies for breast cancer patients, as a single agent or rational co-target, which will be explored in depth in this review.

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Section: Fgfr Signalling In Health and Diseasementioning

confidence: 99%

Fibroblast growth factor receptor signalling dysregulation and targeting in breast cancer

Francavilla

O'Brien

2022

Open Biol.

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“…Pluripotent stem cells provide another characteristic, differentiation propensity, although it is difficult to quantify. Previously, we developed a spontaneous differentiation method to quantify the differentiation propensity of pluripotent stem cells using 5% FBS and RNA-seq 8 . In this study, we demonstrated that the differentiation propensity can serve as an indicator of changes in cellular properties using this method.…”

Section: Discussionmentioning

confidence: 99%

“…To investigate whether enhanced ERK activity in DUSP6-depleted cells affects their differentiation propensity, we induced WT and DUSP6 KO cells using the spontaneous differentiation method (Fig. 5A,B) 8 . To validate the method, we analyzed the differentiation propensity after treating WT cells with reagents inducing three germ layers: activin A for endoderm, CHIR99021 for endo-and mesoderm and SB431542/dorsomorphin for ectoderm [38][39][40][41] .…”

Section: Elevated Erk Activity Causes Tilting Of Differentiation Prop...mentioning

confidence: 99%

“…Various culture conditions have been developed to obtain high-quality hPSCs for clinical applications 3 – 6 . Studies have shown that culture medium can influence the differentiation potential and propensity of pluripotent stem cells 7 , 8 . Furthermore, passaging methods may affect the hPSC properties since these cells grow in colonies and single-cell dissociation causes cell death 2 , 9 .…”

Section: Introductionmentioning

confidence: 99%

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DUSP6 is a memory retention feedback regulator of ERK signaling for cellular resilience of human pluripotent stem cells in response to dissociation

Yoo

et al. 2023

Sci Rep

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Cultured human pluripotent stem cells (hPSCs) grow as colonies that require breakdown into small clumps for further propagation. Although cell death mechanism by single-cell dissociation of hPSCs has been well defined, how hPSCs respond to the deadly stimulus and recover the original status remains unclear. Here we show that dissociation of hPSCs immediately activates ERK, which subsequently activates RSK and induces DUSP6, an ERK-specific phosphatase. Although the activation is transient, DUSP6 expression persists days after passaging. DUSP6 depletion using the CRISPR/Cas9 system reveals that DUSP6 suppresses the ERK activity over the long term. Elevated ERK activity by DUSP6 depletion increases both viability of hPSCs after single-cell dissociation and differentiation propensity towards mesoderm and endoderm lineages. These findings provide new insights into how hPSCs respond to dissociation in order to maintain pluripotency.

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“…DUSP6 is a cytoplasmic DUSP known to catalyze the removal of phosphate groups from threonine and tyrosine residues on Erk1/2 [12]. Previous studies have identified essential roles of DUSP6 in heart development [14], diet-induced obesity [15][16][17], metabolism [18,19], T cell differentiation [20], and the pluripotency of embryonic stem cells [21,22]. However, the role of DUSP6 in cerebral ischemia remains elusive.…”

Section: Introductionmentioning

confidence: 99%

DUSP6 Deficiency Attenuates Neurodegeneration after Global Cerebral Ischemia

Weng

Huang

Chiang

et al. 2023

IJMS

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Transient global cerebral ischemia (tGCI) resulting from cardiac arrest causes selective neurodegeneration in hippocampal CA1 neurons. Although the effect is clear, the underlying mechanisms directing this process remain unclear. Previous studies have shown that phosphorylation of Erk1/2 promotes cell survival in response to tGCI. DUSP6 (also named MKP3) serves as a cytosolic phosphatase that dephosphorylates Erk1/2, but the role of DUSP6 in tGCI has not been characterized. We found that DUSP6 was specifically induced in the cytoplasm of hippocampal CA1 neurons 4 to 24 h after tGCI. DUSP6-deficient mice showed normal spatial memory acquisition and retention in the Barnes maze. Impairment of spatial memory acquisition and retention after tGCI was attenuated in DUSP6-deficient mice. Neurodegeneration after tGCI, revealed by Fluoro-Jade C and H&E staining, was reduced in the hippocampus of DUSP6-deficient mice and DUSP6 deficiency enhanced the phosphorylation and nuclear translocation of Erk1/2 in the hippocampal CA1 region. These data support the role of DUSP6 as a negative regulator of Erk1/2 signaling and indicate the potential of DUSP6 inhibition as a novel therapeutic strategy to treat neurodegeneration after tGCI.

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Simple differentiation method using FBS identifies DUSP6 as a marker for fine-tuning of FGF-ERK signaling activity in human pluripotent stem cells

Cited by 3 publications

References 34 publications

Fibroblast growth factor receptor signalling dysregulation and targeting in breast cancer

Fibroblast growth factor receptor signalling dysregulation and targeting in breast cancer

DUSP6 is a memory retention feedback regulator of ERK signaling for cellular resilience of human pluripotent stem cells in response to dissociation

DUSP6 Deficiency Attenuates Neurodegeneration after Global Cerebral Ischemia

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