Kindlin-1 Regulates Epidermal Growth Factor Receptor Signaling.

Abstract

Kindler syndrome is an autosomal recessive genodermatosis that results from mutations in the FERMT1 gene encoding t kindlin-1. Kindlin-1 localizes to focal adhesion and is known to contribute to the activation of integrin receptors. Most cases of Kindler syndrome show a reduction or complete absence of kindlin-1 in keratinocytes, resulting in defective integrin activation, cell adhesion, and migration. However, roles for kindlin-1 beyond integrin activation remain poorly defined. In this study we show that skin and keratinocytes from Kindler syndrome patients have significantly reduced expression levels of the EGFR, resulting in defective EGF-dependent signaling and cell migration. Mechanistically, we show that kindlin-1 can associate directly with EGFR in vitro and in keratinocytes in an EGF-dependent, integrin-independent manner and that formation of this complex is required for EGF-dependent migration. We further show that kindlin-1 acts to protect EGFR from lysosomal-mediated degradation. This shows a new role for kindlin-1 that has implications for understanding Kindler syndrome disease pathology.

• Authors: Magdalene Michael, Rumena Begum, Grace K Chan, Austin J Whitewood, Daniel R Matthews, Benjamin T Goult, John A McGrath, Maddy Parsons
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 139 Issue 2 Pg. 369-379 (02 2019) ISSN: 1523-1747 [Electronic] United States
• PMID: 30248333 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Video-Audio Media)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• EGF Family of Proteins
• FERMT1 protein, human
• Membrane Proteins
• Neoplasm Proteins
• EGFR protein, human
• ErbB Receptors

Topics

• Blister (genetics, pathology)
• Cell Line
• Cell Movement
• EGF Family of Proteins (metabolism)
• Epidermolysis Bullosa (genetics, pathology)
• ErbB Receptors (metabolism)
• Humans
• Keratinocytes (pathology)
• Lysosomes (metabolism)
• Membrane Proteins (genetics, metabolism)
• Neoplasm Proteins (genetics, metabolism)
• Periodontal Diseases (genetics, pathology)
• Photosensitivity Disorders (genetics, pathology)
• Proteolysis
• Signal Transduction
• Skin (pathology)