An essential role of CBL and CBL-B ubiquitin ligases in mammary stem cell maintenance

Mohapatra, Bhopal; Zutshi, Neha; An, Wei; Goetz, Benjamin T.; Arya, Priyanka; Bielecki, Timothy A.; Mustaq, Insha; Storck, Matthew D.; Meza, Jane L.; Band, Vimla

doi:10.1242/jcs.203992

Cited by 3 publications

(3 citation statements)

References 33 publications

(41 reference statements)

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“…Indeed, expression of the oncogenic mutant PDGFRα Asp842Val, which localizes to the Golgi 239 and is the most common PDGFRα mutation in gastrointestinal stromal tumours 259 , promotes ciliary disassembly and cell proliferation by phenocoyping PDGF-DD-mediated signalling 246 . Furthermore, rapamycin-mediated inhibition of mTOR signalling, which is upregulated in cells deficient in both c-CBL and CBL-b 260 , rescues PDGF-AA–mediated signalling in IFT88 and IFT172 mutant fibroblasts that are devoid of primary cilia 250 , although further studies are required to understand the relationship between aberrant mTOR signalling and mislocalization of PDGFRα in the context of ciliary signalling and tumorigenesis. Finally, INPP5E, was suggested to control ciliary PDGFRα signaling by inhibiting PDGF-mediated AKT activation 261, 262, 263 .…”

Section: Ciliary Rtk Signallingmentioning

confidence: 99%

Cellular signalling by primary cilia in development, organ function and disease

et al. 2019

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Primary cilia project in a single copy from the surface of most vertebrate cell types; they detect and transmit extracellular cues to regulate diverse cellular processes during development and to maintain tissue homeostasis. The sensory capacity of primary cilia relies on the coordinated trafficking and temporal localization of specific receptors and associated signal transduction modules in the cilium. The canonical hedgehog (HH) pathway, for example, is a bona fide ciliary signalling system that regulates cell fate and self-renewal in development and tissue homeostasis. Specific receptors and associated signal transduction proteins can also localize to primary cilia in a cell type-dependent manner; available evidence suggests that the ciliary constellation of these proteins can temporally change to allow the cell to adapt to specific developmental and homeostatic cues. Consistent with important roles for primary cilia in signalling, mutations that lead to their dysfunction underlie a pleiotropic group of diseases and syndromic disorders termed ciliopathies, which affect many different tissues and organs of the body. In this review we highlight central mechanisms by which primary cilia coordinate HH, G-protein-coupled receptor, WNT, receptor tyrosine kinase and TGFβ/BMP signalling, and illustrate how defects in the balanced output of ciliary signalling events are coupled to developmental disorders and disease progression. Opening section The primary cilium is a microtubule-based, non-motile organelle that extends as a solitary unit from the basal body (derived from the centrosomal mother centriole of most cell types

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Section: Ciliary Rtk Signallingmentioning

confidence: 99%

Cellular signalling by primary cilia in development, organ function and disease

et al. 2019

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“…They are interlinked and opposing signalling pathways (González et al, 2020). Restrained mTOR activity is reported previously to be required for self-renewal and differentiation of mammary stem cells (Mohapatra et al, 2017). We and others have previously shown that AMPK activation leads to inhibiton of mTOR signaling in suspension (Saha et al, 2018a).…”

Section: Discussionmentioning

confidence: 64%

AMP-activated protein kinase promotes breast cancer stemness and drug resistance

Andugulapati

Sundararaman

Lahiry

et al. 2022

Disease Models &Amp; Mechanisms

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Breast Cancer Stem Cells (BCSCs) are a major cause of therapy resistance and tumour progression. Currently, their regulation is not entirely understood. Previous work from our lab demonstrated context-specific pro-tumorigenic role of AMP-activated protein kinase (AMPK) in breast cancer cell survival under anchorage-deprivation and mammosphere formation hallmarks of BCSCs. We therefore investigated the role of AMPK in the maintenance of BCSC state/function. AMPK depletion reduces serial sphere formation in vitro and tumour initiation in vivo. Intriguingly, tumour-derived cell analysis using stem cell markers and functional assays revealed that AMPK is required for the maintenance of BCSC population in vivo. AMPK promotes the expression of stemness genes like Nanog, Sox2 and Bmi1 through the transcriptional upregulation of Twist via promoter acetylation. Further, AMPK-driven stemness plays a critical role in resistance to doxorubicin. Significantly, we found that AMPK activity increased after chemotherapy in patient-derived tumour samples alongside an increase in stemness markers. Importantly, AMPK depletion sensitises mice tumours to doxorubicin treatment. Our work indicates that targeting AMPK in conjunction with regular chemotherapy is likely to reduce the stem cell pool and improve chemosensitivity in breast cancers.

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“…Although such organoids generally comprise the epithelial niche alone, Jamieson et al (2017) report in this issue the formation of mammary organoids from the adult mammary epithelium comprising both a secretory epithelium and a surrounding myoepithelial population. A second paper using mammary organoids identifies novel signalling requirements for epithelial stem cell maintenance during development and remodelling (Mohapatra et al, 2017). A non-epithelial population, the human umbilical cord-borne fibroblast, is also reported as capable of creating its own ossicle-bounded, marrow-forming niche (Pievani et al, 2017).…”

Section: Organoids For New Tissue Types and Improvements On Previous mentioning

confidence: 99%

Organoids: a Special Issue

Little

2017

Development

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An essential role of CBL and CBL-B ubiquitin ligases in mammary stem cell maintenance

Abstract: There was an error in Development (2018Development ( ) 144, dev138164 (doi: 10.1242.One of the author names was spelled incorrectly. The online version has been corrected. The authors apologise to readers for this mistake.

Cited by 3 publications

References 33 publications

Cellular signalling by primary cilia in development, organ function and disease

Cellular signalling by primary cilia in development, organ function and disease

AMP-activated protein kinase promotes breast cancer stemness and drug resistance

Organoids: a Special Issue

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