NF2/Merlin mediates contact-dependent inhibition of EGFR mobility and internalization via cortical actomyosin

Chiasson-MacKenzie, Christine; Morris, Zachary S.; Baca, Quentin; Morris, Brett A.; Coker, Joanna; Mirchev, Rossen; Jensen, Anne Eeg; Carey, Thomas; Stott, Shannon L.; Golan, David E.; McClatchey, Andrea I.

doi:10.1083/jcb.201503081

Cited by 57 publications

(69 citation statements)

References 61 publications

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“…Although it has been reported almost 20 years ago that ERBB2 can inhibit the transcription of the E-cadherin gene [22], functional interactions between E-cadherin and ERBB2 or ERBB3 remained largely unexplored. We also did not observe any influence of the ERBB2 or ERBB3 status on the levels of Merlin, another protein known to affect EGFR [23] as well as ERBB2 and ERBB3 [24] in the context of contact-dependent inhibition of proliferation. While EGFR and E-cadherin behaved as expected upon increasing confluence, no noteworthy alteration was observed regarding ERBB2 or ERBB3.…”

Section: Discussioncontrasting

confidence: 48%

CRISPR‐assisted receptor deletion reveals distinct roles for ERBB2 and ERBB3 in skin keratinocytes

Dahlhoff¹,

Gaborit

Bultmann³

et al. 2017

The FEBS Journal

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While the epidermal growth factor receptor (EGFR) is an established regulator of skin development and homeostasis, the functions of the related tyrosine kinase receptors ERBB2 and ERBB3 in this tissue have only recently been examined. Previously reported, skin-specific deletion of each of these receptors in mice resulted in similar defects in keratinocyte proliferation and migration, resulting in impaired wound healing and tumorigenesis. Because both ERBB2 and ERBB3 are targets for treating an array of cancer types, it is important to examine the consequences of receptor inhibition in human keratinocytes. Here, we employed the CRISPR/Cas9 technology to generate HaCaT cells (an established human keratinocyte cell line) lacking ERBB2 or ERBB3. HaCaT clones lacking ERBB2 or ERBB3 showed comparable reductions in cell proliferation as assessed by BrdU staining. Apoptosis, in contrast, was reduced in ERBB3-deficient HaCaT cells only. Assessment of cell migration using a wound healing (scratch) assay showed that the closure of the wound gaps was completed by 48 h in mock and in ERBB3 knockout clones. In contrast, this process was considerably delayed in ERBB2 knockout clones, and a complete closure of the gap in the latter cells did not occur before 72 h. In conclusion, both ERBB2 and ERBB3 are essential for normal proliferation of skin keratinocytes, but in contrast to ERBB3, ERBB2 is essential for migration of human keratinocytes. These observations might bear significance to patient adverse effects of therapeutic agents targeting ERBB2 and ERBB3.

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Section: Discussioncontrasting

confidence: 48%

CRISPR‐assisted receptor deletion reveals distinct roles for ERBB2 and ERBB3 in skin keratinocytes

Dahlhoff¹,

Gaborit

Bultmann³

et al. 2017

The FEBS Journal

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“…The tumor suppressor Merlin, encoded by the gene neurofibromatosis type 2 (NF2) is responsible for the regulation of EGFR in response to cell contact [108]. The mechanism of this occurrence is not yet understood but it was observed that Merlin binds to EGFR, blocking its internalization and this might immobilize the EGFR on the plasma membrane and stabilize cell junctions [108]. NF2 mutations are found in different pathologies, especially in malignant mesothelioma and Neurofibromatosis type 2.…”

Section: Hallmarking Cancermentioning

confidence: 99%

Integrins in the Spotlight of Cancer

Bianconi

Unseld

Prager

2016

IJMS

130

110

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Integrins are heterodimeric cell surface receptors that bind to different extracellular ligands depending on their composition and regulate all processes which enable multicellular life. In cancer, integrins trigger and play key roles in all the features that were once described as the Hallmarks of Cancer. In this review, we will discuss the contribution of integrins to these hallmarks, including uncontrolled and limitless proliferation, invasion of tumor cells, promotion of tumor angiogenesis and evasion of apoptosis and resistance to growth suppressors, by highlighting the latest findings. Further on, given the paramount role of integrins in cancer, we will present novel strategies for integrin inhibition that are starting to emerge, promising a hopeful future regarding cancer treatment.

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“…This phenomenon may not be restricted to Drosophila embryos. The increased contractile actomyosin on the apical cortex of human cell lines deficient for the cortex actin regulator Merlin is associated with a condensation of adherens junctions toward the apical surface, suggesting that the response of adherens junctions to cortical tension can be of general significance (Chiasson-MacKenzie et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Myosin-dependent remodeling of adherens junctions protects junctions from Snail-dependent disassembly

Wieschaus¹,

Weng²

2016

J Gen Physiol

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NF2/Merlin mediates contact-dependent inhibition of EGFR mobility and internalization via cortical actomyosin

Abstract: Merlin and Ezrin are central to a mechanism whereby mechanical forces transduced across the apical actomyosin cytoskeleton from cell junctions control the mobility and internalization of EGFR, providing novel insight into how cells inhibit mitogenic signaling in response to cell contact.

Cited by 57 publications

References 61 publications

CRISPR‐assisted receptor deletion reveals distinct roles for ERBB2 and ERBB3 in skin keratinocytes

CRISPR‐assisted receptor deletion reveals distinct roles for ERBB2 and ERBB3 in skin keratinocytes

Integrins in the Spotlight of Cancer

Myosin-dependent remodeling of adherens junctions protects junctions from Snail-dependent disassembly

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