Maintenance of Stem Cell Niche Integrity by a Novel Activator of Integrin Signaling

Lee, Joo Yeun; Chen, Jessica Y.; Shaw, Jillian L.; Chang, Karen

doi:10.1371/journal.pgen.1006043

Cited by 14 publications

(14 citation statements)

References 71 publications

(97 reference statements)

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“…To address this possibility, we inhibited integrin signaling using a temperature-sensitive allele of Integrin β (mys [ts1]) and monitored the localization of InR. Incubation at the restrictive temperature for 8 h caused a decrease in the overall level of Integrin β, consistent with previous studies (Bunch et al 1992;Beumer et al 1999;Lee et al 2016). Under these conditions, the plasma membrane lo-calization of InR was decreased (Fig.…”

Section: Localization Of Insulin Signaling Components Is Regulated Bysupporting

confidence: 80%

Mechanical stress regulates insulin sensitivity through integrin-dependent control of insulin receptor localization

2018

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Insulin resistance, the failure to activate insulin signaling in the presence of ligand, leads to metabolic diseases, including type 2 diabetes. Physical activity and mechanical stress have been shown to protect against insulin resistance, but the molecular mechanisms remain unclear. Here, we address this relationship in the larval fat body, an insulin-sensitive organ analogous to vertebrate adipose tissue and livers. We found that insulin signaling in fat body cells is abolished in the absence of physical activity and mechanical stress even when excess insulin is present. Physical movement is required for insulin sensitivity in both intact larvae and fat bodies cultured ex vivo. Interestingly, the insulin receptor and other downstream components are recruited to the plasma membrane in response to mechanical stress, and this membrane localization is rapidly lost upon disruption of larval or tissue movement. Sensing of mechanical stimuli is mediated in part by integrins, whose activation is necessary and sufficient for mechanical stress-dependent insulin signaling. Insulin resistance develops naturally during the transition from the active larval stage to the immotile pupal stage, suggesting that regulation of insulin sensitivity by mechanical stress may help coordinate developmental programming with metabolism.

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Section: Localization Of Insulin Signaling Components Is Regulated Bysupporting

confidence: 80%

Mechanical stress regulates insulin sensitivity through integrin-dependent control of insulin receptor localization

2018

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“…The importance of SCs for hub homeostasis described here adds to the observation that Shriveled, secreted by somatic cells and GSCs, contributes to hub maintenance during aging [38]. Our findings also correlate with a reversible plasticity of the female niche modulated by diet and age [39].…”

Section: Discussionsupporting

confidence: 75%

YAP/Yorkie in the germline modulates the age-related decline of germline stem cells and niche cells

et al. 2019

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The properties and behaviour of stem cells rely heavily on signaling from the local microenvironment. At the apical end of Drosophila testis, self-renewal and differentiation of germline stem cells (GSCs) are tightly controlled by distinct somatic cells that comprise a specialised stem cell niche known as the hub. The hub maintains GSC homeostasis through adhesion and cell signaling. The Salvador/Warts/Hippo (SWH) pathway, which suppresses the transcriptional co-activator YAP/Yki via a kinase cascade, is a known regulator of stem cell proliferation and differentiation. Here, we show that increasing YAP/Yki expression in the germline, as well as reducing Warts levels, blocks the decrease of GSC numbers observed in aging flies, with only a small increase on their proliferation. An increased expression of YAP/Yki in the germline or a reduction in Warts levels also stymies an age-related reduction in hub cell number, suggesting a bilateral relationship between GSCs and the hub. Conversely, RNAi-based knockdown of YAP/Yki in the germline leads to a significant drop in hub cell number, further suggesting the existence of such a SC-to-niche relationship. All together, our data implicate the SWH pathway in Drosophila GSC maintenance and raise questions about its role in stem cell homeostasis in aging organisms.

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“…Finally, it will be interesting to determine if UPR-dependent regulation of secretory chaperones such as ERdj3 have non-proteostasis roles in regulating organismal physiology. For example, secreted ERdj3 is involved in multiple signaling pathways during development [49, 50]. This suggests that UPR-dependent regulation of ERdj3 secretion could function as an extracellular signal to coordinate organismal physiology during ER stress through mechanisms such as the non-cell autonomous UPR signaling observed in C. elegans [51].…”

Section: Influencing Downstream Secretory Proteostasis Environments Tmentioning

confidence: 99%

Regulating Secretory Proteostasis through the Unfolded Protein Response: From Function to Therapy

Plate

Wiseman

2017

Trends in Cell Biology

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SUMMARY Imbalances in secretory proteostasis induced by genetic, environmental or aging related insults are pathologically associated with etiologically diverse protein misfolding diseases. To protect the secretory proteome from these insults, organisms evolved stress-responsive signaling pathways that regulate the composition and activity of biologic pathways involved in secretory proteostasis maintenance. The most prominent of these is the endoplasmic reticulum (ER) Unfolded Protein Response (UPR), which functions to regulate ER proteostasis in response to ER stress. While the signaling mechanisms involved in UPR activation are well-defined, the impact of UPR activation on secretory proteostasis is only becoming clear. Here, we highlight recent reports defining how activation of select UPR signaling pathways influences proteostasis within the ER and downstream secretory environments. Furthermore, we describe recent evidence that highlights the therapeutic potential for targeting UPR signaling pathways to correct pathologic disruption in secretory proteostasis associated with diverse types of protein misfolding diseases.

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Maintenance of Stem Cell Niche Integrity by a Novel Activator of Integrin Signaling

Cited by 14 publications

References 71 publications

Mechanical stress regulates insulin sensitivity through integrin-dependent control of insulin receptor localization

Mechanical stress regulates insulin sensitivity through integrin-dependent control of insulin receptor localization

YAP/Yorkie in the germline modulates the age-related decline of germline stem cells and niche cells

Regulating Secretory Proteostasis through the Unfolded Protein Response: From Function to Therapy

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