Cytoskeleton protein 4.1R suppresses murine keratinocyte cell hyperproliferation via activating the Akt/ERK pathway in an EGFR-dependent manner.

Abstract:

:The correct functioning of epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, is required for normal skin development and homeostasis. Cellular hyperproliferation induced by dysregulation of EGFR is tightly associated with structural and functional defects of hair follicles, skin lesions, and tumorigenesis. However, a number of questions still remain regarding the mechanism of EGFR activation and signaling. Here, we report that 4.1R, a member of the membrane-cytoskeleton linker FERM family proteins, plays critical roles in EGFR activation and signaling in keratinocytes. We demonstrated that knockout of 4.1R augments the excessive proliferation potential of keratinocytes by immunohistochemical analysis using murine skin samples. 4.1R-/- keratinocytes display enhanced EGFR-mediated Akt/ERK signaling by upregulating EGFR expression and phosphorylation, which can be reversed by either EGFR or MEK phosphorylation inhibitors. Mechanistically, coimmunoprecipitation and immunofluorescent staining results confirmed that 4.1R can impair the activation of EGFR through direct binding to EGFR and reduce the downstream signaling. Taken together, a deficiency of 4.1R would therefore serve to sustain aberrant EGFR-mediated cellular signaling, leading to hyperproliferation. Our findings highlight the role of 4.1R in the regulation of EGFR signaling in keratinocytes and suggest that 4.1R acts as a novel regulator for EGFR activation.

journal_name

Exp Cell Res

authors

Chen L,Wang T,Ji X,Ding C,Liang T,Liu X,Lu J,Guo X,Kang Q,Ji Z

doi

10.1016/j.yexcr.2019.111648

subject

Has Abstract

pub_date

2019-11-15 00:00:00

pages

111648

issue

2

eissn

0014-4827

issn

1090-2422

pii

S0014-4827(19)30515-4

journal_volume

384

pub_type

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