# Role of keratin intermediate filaments in skin epithelial architecture and homeostasis

> **NIH NIH R56** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $428,872

## Abstract

ABSTRACT
 Keratins are the most abundant proteins in surface epithelia, in which they occur as a cytoplasmic
network of 10 nm wide intermediate filaments (IFs). Keratins are encoded by an evolutionarily conserved family
of 54 genes subdivided into two major types (I and II). Pairwise regulation of type I and type II keratin genes in
epithelia reflects a strict heteropolymerization requirement during keratin intermediate filament assembly. Pairs
of keratin genes are individually regulated in an epithelial tissue-type and differentiation-specific fashion, the
functional basis of which is only partly understood. A major role fulfilled by keratin IFs is to act as resilient yet
pliable scaffolds that endow epithelial cells and tissues with the ability to sustain various types of stress. Many
additional functions that are non-mechanical in nature and manifested in a keratin protein-specific and context-
dependent fashion, have been identified by us and other researchers in recent years. Mutations affecting the
coding sequence of keratins account for a large number of genetically-determined epithelial disorders.
 In studies supported by this project, we recently discovered that keratin-dependent disulfide bonding
plays an important role towards the intracellular organization and steady-state dynamics of keratin filaments in
progenitor basal keratinocytes of epidermis, with an associated impact on the balance between proliferation
and differentiation, and skin barrier function. The latter entails a powerful interplay between disulfide bonding
mediated by residue cysteine 367 (C367) in keratin 14 (K14), the adaptor protein 14-3-3sigma, and YAP1, a
terminal effector of Hippo signaling. Because residue C367 in human K14 is conserved in several additional
type I keratins expressed in crucial cellular settings in skin epithelia we propose, as an overarching hypothesis,
that keratins act as general regulators of Hippo signaling with an associated impact on skin tissue homeostasis
and function. In Aim 1, we will test the hypothesis that residue C401 in keratin 10 is responsible for proper
regulation of YAP1 and Hippo signaling in the suprabasal differentiating layers of epidermis. In Aim 2, we will
test the hypothesis that residue C336 in keratin 17 regulates YAP1 and Hippo signaling and the balance
between proliferation and differentiation in hair follicles, sweat glands, tooth, and possibly in other ectoderm-
derived epithelial appendages. In Aim 3 we will map the binding interface between keratins and 14-3-3sigma
and define the molecular basis for the regulation the keratin/14-3-3 interactions. Finally, in Aim 4, we will test
the possibility that keratin-dependent disulfide bonding fulfills additional roles in skin epithelia in vivo. The
proposed body of work is highly original, lies on a robust premise supported by substantive evidence, and is
poised to significantly advance our understanding of the significance of keratin proteins in vivo as well as the
pa...

## Key facts

- **NIH application ID:** 10226580
- **Project number:** 2R56AR042047-24A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Pierre Coulombe
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $428,872
- **Award type:** 2
- **Project period:** 1995-06-15 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226580

## Citation

> US National Institutes of Health, RePORTER application 10226580, Role of keratin intermediate filaments in skin epithelial architecture and homeostasis (2R56AR042047-24A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10226580. Licensed CC0.

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