An SH3PX1-Dependent Endocytosis-Autophagy Network Restrains Intestinal Stem Cell Proliferation by Counteracting EGFR-ERK Signaling

Zhang, Peng; Holowatyj, Andreana N.; Roy, Taylor; Pronovost, Stephen M.; Marchetti, M. A.; Liu, Hanbin; Ulrich, Cornelia M.; Edgar, Bruce A.

doi:10.1016/j.devcel.2019.03.029

Cited by 68 publications

(96 citation statements)

References 83 publications

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“…This study demonstrated that blockages within the endocytosis-autophagy network stabilize ligand-activated EGFRs. This blocks the recycling of EGFRs to the plasma membrane and, in turn, counteracts EGFR signaling (Zhang et al, 2019). However, the biological functions and the physiological significance of the endocytic pathway in the context of ISC aging remain inadequately understood.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, this study demonstrated that endocytosis works downstream of ALA in ISCs to protect the degeneration of intestinal function upon aging. A recent study indicated EGFR signaling as the main trigger for ISC overproliferation when the endocytosis-autophagy network was disturbed (Zhang et al, 2019). Therefore, this study investigated the EGFR activity of ISCs of Drosophila in response to ALA administration by monitoring the dpERK level.…”

Section: Ala Administration Rejuvenates Aged Iscs By Modulating Endocmentioning

confidence: 99%

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Lipoic acid rejuvenates aged intestinal stem cells by preventing age‐associated endosome reduction

Qiao

Zhuo

et al. 2020

EMBO Reports

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The age-associated decline of adult stem cell function is closely related to the decline in tissue function and age-related diseases. However, the underlying mechanisms that ultimately lead to the observed functional decline of stem cells still remain largely unexplored. This study investigated Drosophila midguts and found a continuous downregulation of lipoic acid synthase, which encodes the key enzyme for the endogenous synthesis of alpha-lipoic acid (ALA), upon aging. Importantly, orally administration of ALA significantly reversed the age-associated hyperproliferation of intestinal stem cells (ISCs) and the observed decline of intestinal function, thus extending the lifespan of Drosophila. This study reports that ALA reverses age-associated ISC dysfunction by promoting the activation of the endocytosis-autophagy network, which decreases in aged ISCs. Moreover, this study suggests that ALA may be used as a safe and effective anti-aging compound for the treatment of ISCdysfunction-related diseases and for the promotion of healthy aging in humans.

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Section: Discussionmentioning

confidence: 99%

Section: Ala Administration Rejuvenates Aged Iscs By Modulating Endocmentioning

confidence: 99%

Lipoic acid rejuvenates aged intestinal stem cells by preventing age‐associated endosome reduction

Qiao

Zhuo

et al. 2020

EMBO Reports

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“…Because homeostatic control of proliferation occurs broadly in the animal kingdom and because regulators of stem cell proliferation and homeostasis are highly conserved (ERK/MAPK and IIS, see Introduction), these regulators may similarly combine to orchestrate stem cell proliferation rates in diverse stem cell populations. Consistent with this, GSC proliferation in Drosophila is stimulated by nutrient uptake via IIS signaling 33 , while homeostatic regulation of intestinal stem cells occurs through ERK/MAPK regulation 61 .…”

Section: Discussionmentioning

confidence: 56%

Non-autonomous regulation of germline stem cell proliferation by somatic MPK-1/MAPK activity inC. elegans

Robinson-Thiewes

Dufour

Martel

et al. 2020

Preprint

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Extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) is a major positive regulator of cell proliferation that is often upregulated in cancer. Yet few studies have addressed ERK/MAPK regulation of proliferation within a complete organism. The C. elegans ERK/MAPK ortholog MPK-1 is best known for its control of somatic organogenesis and germline differentiation, but it also stimulates germline stem cell proliferation. Here we identify tissue-specific MPK-1 isoforms and characterize their distinct roles in germline function. The germline-specific MPK-1B isoform promotes germline differentiation, but has no apparent role in germline stem cell proliferation. By contrast, the soma-specific MPK-1A isoform promotes germline proliferation non-autonomously. Indeed, MPK-1A functions in the intestine or somatic gonad to promote germline proliferation, independently of its other known roles. We propose that a non-autonomous role of ERK/MAPK in stem cell proliferation may be conserved across species and other tissue types, with major clinical implications for cancer and other diseases.

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“…Our studies reveal that ISCautonomous defects in the endocytosis-autophagy network (including shi/dynamin, Rab5, Rab7, SH3PX1, Atg1, Atg5, Atg6, Atg7, Atg8a, Atg9, Atg12, Atg16 and Syx17) release ISC proliferation without regulating differentiation, potentially increasing cancer risk. We provide a detailed functional analysis of how a conserved process (autophagic flux) controls a classical growth signaling pathway (Egfr-Ras85D-mitogenactivated protein kinase), and how genes in this process (some poorly characterized, like SH3PX1) can be anti-proliferative and tumor-suppressive [1].…”

Section: Isc-autonomous Autophagy Defects Release Stem Cell Proliferamentioning

confidence: 99%

Tumor suppressive autophagy in intestinal stem cells controls gut homeostasis

et al. 2019

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We recently found that rerouting intracellular vesicle traffic by suppressing macroautophagy/autophagy or endocytosis genes drastically deregulates Drosophila intestinal stem cell (ISC) proliferation, leading to massive gut hyperplasia that has a negative impact upon lifespan. Beginning with the poorly characterized Snx (sorting nexin) genes, we surveyed a broad set of genes in the endocytosis-autophagy network and found that most of them have this effect. We then discovered that deregulated Egfr-Ras85D/Ras1mitogen-activated protein kinase signaling is the primary trigger for ISC proliferation upon disruption of this network and determined that in the mutants, ligand-activated receptors were stabilized and recycled to the cell surface via Rab11-dependent endosomes, rather than being degraded via autophagosomes. We profiled the mutational landscape for orthologous network genes in human cancers using The Cancer Genome Atlas (TCGA), and revealed strong, novel associations with distinct genomic and epigenomic subtypes of colorectal cancer.

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An SH3PX1-Dependent Endocytosis-Autophagy Network Restrains Intestinal Stem Cell Proliferation by Counteracting EGFR-ERK Signaling

Abstract: Highlights d A Drosophila SH3PX1-dependent endocytosis-autophagy network restrains ISC division d Endocytosis and autophagy control ISC division by counteracting EGFR-ERK activity d Genes in endocytosis and autophagy are frequently mutated in human cancers

Cited by 68 publications

References 83 publications

Lipoic acid rejuvenates aged intestinal stem cells by preventing age‐associated endosome reduction

Lipoic acid rejuvenates aged intestinal stem cells by preventing age‐associated endosome reduction

Non-autonomous regulation of germline stem cell proliferation by somatic MPK-1/MAPK activity inC. elegans

Tumor suppressive autophagy in intestinal stem cells controls gut homeostasis

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