Receptor Tyrosine Kinase EPHA2 Drives Epidermal Differentiation through Regulation of EGFR Signaling

Bethany E. Perez White; Calvin J. Cable; Bo Shi; Rosa Ventrella; Nihal Kaplan; Aya Kobeissi; Yuya Higuchi; Abhinav Balu; Zachary R. Murphy; Priya Kumar; Spiro Getsios

doi:10.1016/j.jid.2024.01.014

Receptor Tyrosine Kinase EPHA2 Drives Epidermal Differentiation through Regulation of EGFR Signaling

Bethany E. Perez White^*, Calvin J. Cable, Bo Shi, Rosa Ventrella, Nihal Kaplan, Aya Kobeissi, Yuya Higuchi, Abhinav Balu, Zachary R. Murphy, Priya Kumar, Spiro Getsios

^*Corresponding author for this work

Dermatology

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

Intricate signaling systems are required to maintain homeostasis and promote differentiation in the epidermis. Receptor tyrosine kinases are central in orchestrating these systems in epidermal keratinocytes. In particular, EPHA2 and EGFR transduce distinct signals to dictate keratinocyte fate, yet how these cell communication networks are integrated has not been investigated. Our work shows that loss of EPHA2 impairs keratinocyte stratification, differentiation, and barrier function. To determine the mechanism of this dysfunction, we drew from our proteomics data of potential EPHA2 interacting proteins. We identified EGFR as a high-ranking EPHA2 interactor and subsequently validated this interaction. We found that when EPHA2 is reduced, EGFR activation and downstream signaling are intensified and sustained. Evidence indicates that prolonged SRC association contributes to the increase in EGFR signaling. We show that hyperactive EGFR signaling underlies the differentiation defect caused by EPHA2 knockdown because EGFR inhibition restores differentiation in EPHA2-deficient 3-dimensional skin organoids. Our data implicate a mechanism whereby EPHA2 restrains EGFR signaling, allowing for fine tuning in the processes of terminal differentiation and barrier formation. Taken together, we purport that crosstalk between receptor tyrosine kinases EPHA2 and EGFR is critical for epidermal differentiation.

Original language	English (US)
Pages (from-to)	1798-1807.e1
Journal	Journal of Investigative Dermatology
Volume	144
Issue number	8
DOIs	https://doi.org/10.1016/j.jid.2024.01.014
State	Published - Aug 2024

Funding

This work was supported by the National Institutes of Health: K01AR072773 to BEPW, a Skin Biology and Diseases Resource-based Center Grant (P30AR075049), and previous National Institutes of Health training fellowships to BEPW (T32AR060710) and RV (T32GM08061). BEPW also received support from the Dermatology Foundation, the Chicago Biomedical Consortium, and the Northwestern University Clinical and Translational Sciences Institute (National Institutes of Health UL1TR001422). CJC was supported by the Northwestern Undergraduate Research Program. Conceptualization: BEPW, SG; Investigation: BEPW, CJC, RV, NK, BS, AK, YH, AB, ZRM, PK; Visualization: BEPW; Writing – Original Draft Preparation: BEPW; Writing – Review and Editing: BEPW, CJC, RV, NK, BS, AK, YH, AB, ZRM, PK, SG This work was supported by the National Institutes of Health (NIH) [K01AR072773 to B.E.P.W.], a Skin Biology and Diseases Resource-based Center Grant [P30AR075049], and previous NIH training fellowships to B.E.P.W. [T32AR060710] and R.V. [T32GM08061]. B.E.P.W. also received support from the Dermatology Foundation, the Chicago Biomedical Consortium, and the Northwestern University Clinical and Translational Sciences Institute [NIH UL1TR001422]. C.J.C. was supported by the Northwestern Undergraduate Research Program.

Keywords

Barrier function
Epithelial development
Proteomics
Skin organoid
Tight junctions

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Dermatology
Cell Biology

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10.1016/j.jid.2024.01.014

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title = "Receptor Tyrosine Kinase EPHA2 Drives Epidermal Differentiation through Regulation of EGFR Signaling",

abstract = "Intricate signaling systems are required to maintain homeostasis and promote differentiation in the epidermis. Receptor tyrosine kinases are central in orchestrating these systems in epidermal keratinocytes. In particular, EPHA2 and EGFR transduce distinct signals to dictate keratinocyte fate, yet how these cell communication networks are integrated has not been investigated. Our work shows that loss of EPHA2 impairs keratinocyte stratification, differentiation, and barrier function. To determine the mechanism of this dysfunction, we drew from our proteomics data of potential EPHA2 interacting proteins. We identified EGFR as a high-ranking EPHA2 interactor and subsequently validated this interaction. We found that when EPHA2 is reduced, EGFR activation and downstream signaling are intensified and sustained. Evidence indicates that prolonged SRC association contributes to the increase in EGFR signaling. We show that hyperactive EGFR signaling underlies the differentiation defect caused by EPHA2 knockdown because EGFR inhibition restores differentiation in EPHA2-deficient 3-dimensional skin organoids. Our data implicate a mechanism whereby EPHA2 restrains EGFR signaling, allowing for fine tuning in the processes of terminal differentiation and barrier formation. Taken together, we purport that crosstalk between receptor tyrosine kinases EPHA2 and EGFR is critical for epidermal differentiation.",

keywords = "Barrier function, Epithelial development, Proteomics, Skin organoid, Tight junctions",

author = "{Perez White}, {Bethany E.} and Cable, {Calvin J.} and Bo Shi and Rosa Ventrella and Nihal Kaplan and Aya Kobeissi and Yuya Higuchi and Abhinav Balu and Murphy, {Zachary R.} and Priya Kumar and Spiro Getsios",

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year = "2024",

month = aug,

doi = "10.1016/j.jid.2024.01.014",

language = "English (US)",

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T1 - Receptor Tyrosine Kinase EPHA2 Drives Epidermal Differentiation through Regulation of EGFR Signaling

AU - Perez White, Bethany E.

AU - Cable, Calvin J.

AU - Shi, Bo

AU - Ventrella, Rosa

AU - Kaplan, Nihal

AU - Kobeissi, Aya

AU - Higuchi, Yuya

AU - Balu, Abhinav

AU - Murphy, Zachary R.

AU - Kumar, Priya

AU - Getsios, Spiro

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N2 - Intricate signaling systems are required to maintain homeostasis and promote differentiation in the epidermis. Receptor tyrosine kinases are central in orchestrating these systems in epidermal keratinocytes. In particular, EPHA2 and EGFR transduce distinct signals to dictate keratinocyte fate, yet how these cell communication networks are integrated has not been investigated. Our work shows that loss of EPHA2 impairs keratinocyte stratification, differentiation, and barrier function. To determine the mechanism of this dysfunction, we drew from our proteomics data of potential EPHA2 interacting proteins. We identified EGFR as a high-ranking EPHA2 interactor and subsequently validated this interaction. We found that when EPHA2 is reduced, EGFR activation and downstream signaling are intensified and sustained. Evidence indicates that prolonged SRC association contributes to the increase in EGFR signaling. We show that hyperactive EGFR signaling underlies the differentiation defect caused by EPHA2 knockdown because EGFR inhibition restores differentiation in EPHA2-deficient 3-dimensional skin organoids. Our data implicate a mechanism whereby EPHA2 restrains EGFR signaling, allowing for fine tuning in the processes of terminal differentiation and barrier formation. Taken together, we purport that crosstalk between receptor tyrosine kinases EPHA2 and EGFR is critical for epidermal differentiation.

AB - Intricate signaling systems are required to maintain homeostasis and promote differentiation in the epidermis. Receptor tyrosine kinases are central in orchestrating these systems in epidermal keratinocytes. In particular, EPHA2 and EGFR transduce distinct signals to dictate keratinocyte fate, yet how these cell communication networks are integrated has not been investigated. Our work shows that loss of EPHA2 impairs keratinocyte stratification, differentiation, and barrier function. To determine the mechanism of this dysfunction, we drew from our proteomics data of potential EPHA2 interacting proteins. We identified EGFR as a high-ranking EPHA2 interactor and subsequently validated this interaction. We found that when EPHA2 is reduced, EGFR activation and downstream signaling are intensified and sustained. Evidence indicates that prolonged SRC association contributes to the increase in EGFR signaling. We show that hyperactive EGFR signaling underlies the differentiation defect caused by EPHA2 knockdown because EGFR inhibition restores differentiation in EPHA2-deficient 3-dimensional skin organoids. Our data implicate a mechanism whereby EPHA2 restrains EGFR signaling, allowing for fine tuning in the processes of terminal differentiation and barrier formation. Taken together, we purport that crosstalk between receptor tyrosine kinases EPHA2 and EGFR is critical for epidermal differentiation.

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Receptor Tyrosine Kinase EPHA2 Drives Epidermal Differentiation through Regulation of EGFR Signaling

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