# Role of keratin intermediate filaments in skin epithelial differentiation.

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $426,817

## Abstract

ABSTRACT
 Genetically-determined mutations that affect the sequence of keratin proteins account for a large
number of skin epithelial disorders, many of which are rooted in defective cellular mechanics. Keratins are the
most abundant proteins in surface epithelia like epidermis, where they primarily occur as intricate cytoplasmic
networks 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 II keratin genes
in epithelial cells reflects a strict heteropolymerization requirement during IF assembly. Specific pairs of keratin
genes are regulated in an epithelial tissue-type and differentiation-specific fashion. One of the many roles so
far elucidated for keratin IFs is to act as resilient yet pliable scaffolds that endow epithelial cells and tissues
with the ability to sustain various stresses.
 A newly emerging, exciting role for keratin proteins is to regulate epithelial differentiation through the
modulation of Hippo and Notch signaling. We recently discovered that keratin-dependent disulfide bonding
plays a crucial role towards the intracellular organization and steady-state dynamics of keratin filaments in
progenitor keratinocytes of epidermis, with an associated impact on the balance between proliferation and
differentiation. This role entails a delicate interplay between disulfide bonding mediated by a specific residue
known as the “stutter cysteine” in keratin 14 (K14), the adaptor protein 14-3-3sigma, and YAP1, a terminal
effector of Hippo signaling. Since the stutter cysteine in K14 is conserved in several additional type I keratins
expressed in skin epithelia we propose, as an overarching hypothesis, that keratins act as general regulators
of Hippo signaling with an associated impact on differentiation and homeostasis in skin epithelia. In Aim 1, we
will test the hypothesis that the stutter cysteine in K10 is responsible for proper regulation of YAP1 and Hippo
signaling in the differentiating layers of epidermis, with direct relevance for the keratin disorder epidermolytic
hyperkeratosis. In Aim 2 we will map the binding interface between 14-3-3sigma and each of K14 and K10,
define the basis for the regulation the keratin/14-3-3 interactions, and identify the source of the signal that
drives K14- and K10-dependent disulfide bonding in keratinocytes. We will also conduct a high-throughput
screen comparing gene expression, at the single cell level, in control vs. Krt14 C373A transgenic mice, which
exhibit an epidermal differentiation defect coupled to misregulation of YAP1. In Aim 3, finally, we will test the
hypothesis that the stutter cysteine in K17 regulates YAP1 and Hippo signaling and the balance between
proliferation and differentiation in hair follicles, sweat glands, tooth, and possibly in other appendages, with
relevance for the disorder pachyonychia congenita. The proposed body of work lies on...

## Key facts

- **NIH application ID:** 10273570
- **Project number:** 1R01AR079418-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Pierre Coulombe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $426,817
- **Award type:** 1
- **Project period:** 2021-08-09 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10273570

## Citation

> US National Institutes of Health, RePORTER application 10273570, Role of keratin intermediate filaments in skin epithelial differentiation. (1R01AR079418-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10273570. Licensed CC0.

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