ORCID Profile
0000-0002-2102-7339
Current Organisation
Kingston University
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Publisher: Public Library of Science (PLoS)
Date: 15-10-2019
Publisher: The Company of Biologists
Date: 2016
DOI: 10.1242/DEV.133728
Abstract: The skin is a squamous epithelium that is continuously renewed by a population of basal layer stem rogenitor cells and can heal wounds. Here we show that YAP and TAZ are nuclear localised in the basal layer of skin and are elevated upon wound healing. Skin-specific deletion of both YAP and TAZ in adult mice slows proliferation of basal layer cells, leads to hair loss and impairs regeneration after wounding. Contact with the basal extracellular matrix and consequent Integrin-Src signalling is a key determinant of YAP/TAZ nuclear localisation in basal layer cells and in skin tumours. Contact with the basement membrane is lost in differentiating daughter cells, where YAP and TAZ become mostly cytoplasmic. In other types of squamous epithelia and squamous cell carcinomas, a similar control mechanism is present. In contrast, columnar epithelia differentiate an apical domain that recruits CRB3, MERLIN, KIBRA and SAV to induce Hippo signalling and retain YAP/TAZ in the cytoplasm despite contact with the basal layer extracellular matrix. When columnar epithelial tumours lose their apical domain and become invasive, YAP/TAZ becomes nuclear and tumour growth becomes sensitive to the Src inhibitor Dasatinib.
Publisher: eLife Sciences Publications, Ltd
Date: 29-10-2019
DOI: 10.7554/ELIFE.48601
Abstract: Mask family proteins were discovered in Drosophila to promote the activity of the transcriptional coactivator Yorkie (Yki), the sole fly homolog of mammalian YAP (YAP1) and TAZ (WWTR1). The molecular function of Mask, or its mammalian homologs Mask1 (ANKHD1) and Mask2 (ANKRD17), remains unclear. Mask family proteins contain two ankyrin repeat domains that bind Yki/YAP as well as a conserved nuclear localisation sequence (NLS) and nuclear export sequence (NES), suggesting a role in nucleo-cytoplasmic transport. Here we show that Mask acts to promote nuclear import of Yki, and that addition of an ectopic NLS to Yki is sufficient to bypass the requirement for Mask in Yki-driven tissue growth. Mammalian Mask1/2 proteins also promote nuclear import of YAP, as well as stabilising YAP and driving formation of liquid droplets. Mask1/2 and YAP normally colocalise in a granular fashion in both nucleus and cytoplasm, and are co-regulated during mechanotransduction.
Publisher: eLife Sciences Publications, Ltd
Date: 21-06-2018
Publisher: eLife Sciences Publications, Ltd
Date: 20-09-2018
DOI: 10.7554/ELIFE.33304
Abstract: Squamous cell carcinoma (SCC) can progress to malignant metastatic cancer, including an aggressive subtype known as spindle cell carcinoma (spSCC). spSCC formation involves epithelial-to-mesenchymal transition (EMT), yet the molecular basis of this event remains unknown. The transcriptional co-activator YAP undergoes recurrent lification in human SCC and overexpression of YAP drives SCC formation in mice. Here, we show that human spSCC tumours also feature strong nuclear localisation of YAP and overexpression of activated YAP (NLS-YAP-5SA) with Keratin-5 (K5-CreERt) is sufficient to induce rapid formation of both SCC and spSCC in mice. spSCC tumours arise at sites of epithelial scratch wounding, where tumour-initiating epithelial cells undergo EMT to generate spSCC. Expression of the EMT transcription factor ZEB1 arises upon wounding and is a defining characteristic of spSCC in mice and humans. Thus, the wound healing response synergises with YAP to drive metaplastic transformation of SCC to spSCC.
Publisher: eLife Sciences Publications, Ltd
Date: 11-10-2019
Publisher: The Company of Biologists
Date: 2016
DOI: 10.1242/JCS.189076
Abstract: In epithelial tissues, polarisation of microtubules and actin microvilli occurs along the apical-basal axis of each cell, yet how these cytoskeletal polarisation events are coordinated remains unclear. Here we examine the hierarchy of events during cytoskeletal polarisation in Drosophila and human epithelia. Core apical-basal polarity determinants polarise the Spectrin cytoskeleton to recruit the microtubule-binding proteins Patronin (CAMSAP1/2/3 in humans) and Shortstop (Shot MACF1/BPAG1 in humans) to the apical membrane domain. Patronin and Shot then act to polarise microtubules along the apical-basal axis to enable apical transport of Rab11 endosomes by the Nuf-Dynein microtubule motor complex. Finally, Rab11 endosomes are transferred to the MyoV actin motor to deliver the key microvillar determinant Cadherin99C to the apical membrane to organise the biogenesis of actin microvilli.
Publisher: Wiley
Date: 13-05-2016
Abstract: The YAP/TAZ family of transcriptional co-activators drives cell proliferation in epithelial tissues and cancers. Yet, how YAP and TAZ are physiologically regulated remains unclear. Here we review recent reports that YAP and TAZ act primarily as sensors of epithelial cell polarity, being inhibited when cells differentiate an apical membrane domain, and being activated when cells contact the extracellular matrix via their basal membrane domain. Apical signalling occurs via the canonical Crumbs/CRB-Hippo/MST-Warts/LATS kinase cascade to phosphorylate and inhibit YAP/TAZ. Basal signalling occurs via Integrins and Src family kinases to phosphorylate and activate YAP/TAZ. Thus, YAP/TAZ is localised to the nucleus in basal stem rogenitor cells and cytoplasm in differentiated squamous cells or columnar cells. In addition, other signals such as mechanical forces, tissue damage and possibly receptor tyrosine kinases (RTKs) can influence MST-LATS or Src family kinase activity to modulate YAP/TAZ activity.
Publisher: eLife Sciences Publications, Ltd
Date: 11-10-2019
Publisher: The Company of Biologists
Date: 2018
DOI: 10.1242/JCS.221788
Abstract: Human cells can sense mechanical stress acting upon Integrin adhesions and respond by sending the YAP (YAP1) and TAZ (WWTR1) transcriptional co-activators to the nucleus to drive TEAD-dependent transcription of target genes. How Integrin signaling activates YAP remains unclear. Here we identify a key role for the Enigma (PDLIM7) and Enigma-like (PDLIM5) family of PDZ and LIM domain containing proteins in Integrin-mediated mechanotransduction. YAP binds to PDLIM5/7 via its C-terminal PDZ binding motif (PBM), which is essential for full nuclear localization and activity of YAP. Accordingly, silencing of PDLIM5/7 expression reduces YAP nuclear localization, tyrosine phosphorylation, and transcriptional activity. The PDLIM5/7 proteins are recruited from the cytoplasm to Integrin adhesions and F-actin stress fibres in response to force by binding directly to the key stress fibre component alpha-actinin. Thus, forces acting on Integrins recruit Enigma family proteins to trigger YAP activation during mechanotransduction.
Publisher: EMBO
Date: 23-02-2015
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Ahmed Elbediwy.