2. Introduction Keratins are a diverse group of structural
proteins that form the intermediate filament network responsible
for maintaining the structural integrity of keratinocytes. There
are around 30 families of keratin proteins divided into two groups
namely acidic and basic which are arranged in pairs. A total of 54
functional genes exist which codes for these keratin families. 3.
The expression of specific keratin genes is regulated by the
differentiation of epithelial cells within the stratifying squamous
epithelium. Keratins and certain keratin associated proteins are
useful as markers of differentiation because their expression is
both region and differentiation specific. 4. Most of the eukaryotic
cells are composed of cytoskeleton which is made of three
components microfilaments, intermediate filaments, and
microtubules. Among the various families and sub-families of
intermediate filament proteins, keratin is an important type due to
its high molecular diversity. 5. Structure Each keratin is
characterized by a chain of amino acids as the primary structure,
which varies in the number and sequence of amino acid as well as in
polarity, charge and size. The amino acid sequence of a keratin
influences the properties and function of the keratin filament. 6.
Post translational modifications such as the formation of
disulphide bonds, phosphorylation and glycosylation can influence
the conformation of the molecule and formation of keratin
filaments. Keratin filaments have a tripartite secondary structure
consisting of an N-terminal head domain, a central -helical rod
domain and C- terminal tail domain. 7. The keratins are broadly
divided into: Primary keratins are those keratins which are always
synthesized by the epithelial cells on a regular basis, e.g., K8/18
in simple epithelia, K5/14 in stratified epithelia. Secondary
keratins are those types of keratins which are produced by the
epithelial cells in addition to or instead of primary keratins,
e.g., K7/19 in simple epithelia, K15, and K6/16 in stratified
epithelia. Classification 8. Based on distribution: Soft keratin:
Found in the epidermis of skin in the form of flattened
non-nucleated scales that slough continually. The disulfide links
are fewer in number which allows some stretching but returns to
normal upon relaxation of tension. Hard keratin: These are mainly
found in nail, hair cortex, hair cuticle; the keratin type seen at
these sites have very little flexibility owing to the presence of
many cysteine disulfide crosslinks. 9. Based on X-ray diffraction
pattern: Alpha : The X-ray diffraction pattern of this type
resembles that of -helix . The -helix is right handed and has 3.6
residues per turn. The hydrogen bonding occurs within one
polypeptide chain. Beta : The helix is right-handed with an average
of 6 residues. The hydrogen bonding occurs between neighbouring
polypeptide chains. 10. Based on amino acid sequence Type I family
includes keratins numbered 9-20 which are composed of acidic
proteins. Type II family includes keratins numbered 1-8 which are
composed of basic proteins. 11. Based on molecular weight: Low
molecular weight keratins: Include keratins with a molecular weight
of 40kDa. These keratins are mainly distributed in glandular and
simple epithelia. Intermediate molecular weight keratins: Include
keratins with a molecular weight intermediate between 40kDa and
57kDa and are found in stratified epithelia. High molecular weight
keratins: Include keratins with a molecular weight of 57kDa and are
seen in keratinized stratified epithelia. 12. Functions Keratins
fundamentally influence the architecture and mitotic activity of
the epithelial cells. Keratins and associated filaments provide a
scaffold for epithelial cells and tissues to sustain mechanical
stress, maintain their structural integrity, ensure mechanical
resilience, to protect against variations in hydrostatic pressure
and establish cell polarity. 13. Keratins and its filaments are
involved in cell signalling, cell transport, cell
compartmentalization and cell differentiation. Keratin filaments
also influence cell metabolic processes by regulating protein
synthesis and cell growth. Keratins may also be involved in the
transport of membrane bound vesicles in the cytoplasm of the
epithelial cells. 14. Factors regulating Differentiaition Growth
factors like epidermal growth factor, transforming growth factor
alpha and beta Role of adjacent mesenchymal tissue Components of
extracellular matrix Retinoids Calcium 15. Effect of Retinoids on
various keratins Protein Effects K1/10 Reduced expression K13/19
Increased expression K5, K16, K17 Slightly downregulated K4,K5, K14
Not affected Filaggrin Reduced expression Cornified cell envelope
Suppressed Desmosomes Reduced in number 16. Keratin distribution in
epithelia K5 / K14 Basal layer keratinizined & non- keratinized
stratified epithelium K1 / K10 Keratinized epidermis K6 / K16
Spinous layer - keratinized mucosa K4 / K13 Intermediate layer non
keratinized epithelium K19 Basal layer non keratinized epithelium
K9 Suprabasal layer palmar & plantar epidermis 17.
Keratinization disorders of skin Defect Disorder K5 / K14
Epidermolysis bullosa simplex K1 / K10 Epidermolytic Icthyosis K6 /
K16, K17 Pachyonychia congenita K9 Epidermolytic palmoplantar
keratoderma K1 Non-epidermolytic palmoplantar keratoderma K5
Epidermolysis bullosa with mottled pigmentation K4 / K13 White
Sponge Nevus 18. K8 & K18 Keratins K8 & K18 are
co-expressed and constitute the primary keratin of simple
epithelial cells. They are also the sole keratins of hepatocytes,
acinar cells of pancreas and proximal tubular cells of kidney. They
are the first keratins to appear in embryogenesis. 19. K7 & K19
They are the secondary or additional keratins of simple epithelial
cells. They are expressed notably in ductal epithelia of small and
large intestines, gastric foveolar epithelium, mesothelium,
urothelium, as well as basal cells of non keratinizing stratified
squamous epithelia. 20. They are frequently co-expressed. Type I
keratin K19 is the smallest keratin. They are used as tumour
markers. 21. K20 K20 is the simple epithelial keratin with most
restricted expression pattern. They are expressed in the gastric
foveolar epithelium, small and large intestinal epithelium,
urothelium and merkel cells. K20 positivity is predictive of a
primary tumour in the gastrointestinal or pancreatobiliary tract.
22. K5 & K14 K5 & K14 form the primary keratin pair of
keratinocytes of stratified squamous epithelia, including the
epidermis and mucosal non keratinizing stratified squamous
epithelia. In the follicular outer root sheath they are uniformly
expressed throughout all layers. 23. Ultrastructurally, K5/K14
keratin filaments are bundled as tonofilaments and attached to
desmosomes and hemidesmosomes. Mutations of the K5 / K14 gene is
responsible for the blistering disease Epidermolysis bullosa
simplex. 24. K15 K15 keratin is a basal keratinocyte keratin and
hair follicle stem cell marker. In comparison to K5 and K14, K15 is
completely restricted to the basal cell layer of stratified
squamous epithelia. It is also expressed in the basal keratinocytes
of the hair follicle bulge region. 25. K6 & K16 These keratins
are expressed in epidermis of plantar glabrous skin, hair follicle
outer root sheath and companion layer. They are the constitutive
components of nail epithelia. Mutations in K6/K16 give rise to
pachyonychia congenita type I. These keratins are inducible upon
stress, injury or inflammation. 26. K17 K17 is a
basal/myoepithelial cell keratin. It is expressed in myoepithelial
cells of complex tissues, including various glands (sweat glands),
respiratory epithelium and urothelium. It is a prominent component
of the suprabasal cell layers of outer follicular root sheath. 27.
After skin injury, K17 is switched on in regenerating and migrating
epidermal keratinocytes upon wound healing. K17 mutations have been
identified in pachyonychia congenita type II and steatocystoma
muliplex. Like K6/K16, these keratins are also inducible upon
stress, injury or inflammation. 28. K1 & K10 In the epidermis,
the transition of keratinocytes from basal cell layer to suprabasal
spinous cell layer is characterised by a profound change in keratin
expression. This involves a switch from expression of basal cell
keratins ( K5, K14, K15 ) to suprabasal epidermal keratins, k1 and
subsequently K10. 29. Keratin filaments composed of K1/K10 pair
form particularly dense bundles which are so characteristic of
suprabasal epidermal keratinocytes. This imparts mechanical
integrity to the cells and the whole epidermis. K10 specifically
inhibits proliferation and cell cycle progression of keratinocytes.
Loss of K10 leads to increased keratinocyte turnover. 30. Mutations
in K1 and K10 are associated with blistering disorder bullous
congenital icthyosiform erythroderma. Therefore, K1 and K10 are
regarded as keratinization markers of keratinocytes. 31. K9 K9 is a
highly specific keratin of terminally differentiating keratinocytes
of palmoplantar epidermis. Mutations in K9 gene are associated with
skin disorder epidermolytic palmoplantar keratoderma. 32. K2
Keratin specific for advanced terminal differentiation process of
epidermal keratinocytes. It is expressed in the uppermost epidermal
layers - upper stratum spinosum, stratum granulosum. Mutations in
K2 are associated with icthyosis bullosa of Siemens. 33. K3 &
K12 K3/ K12 are the keratin pair of the corneal epithelium. They
are expressed in all corneal epithelial cell layers. Mutations in
these keratins give rise to Meesmanns corneal dystrophy. 34. K4
& K13 They are a highly characteristic keratin pair indicating
mucosal path of keratin differentiation. They are expressed in the
entire suprabasal compartment of mucosal stratified squamous
epithelia. They are absent in the epidermis and adnexa. Mutations
in these keratins cause the disorder white sponge nevus of Cannon.
35. K76 K76 is a highly specific keratin expressed in suprabasal
cell layers of oral masticatory epithelium. They are found in the
slightly orthokeratinized stratified squamous epithelium lining the
gingiva and hard palate. 36. K77 Highly specific keratin restricted
to the luminal cells of eccrine sweat glands. Used as an eccrine
duct marker. 37. Hair follicle specific keratins K25 - 28, K71 - 75
These keratins are specifically expressed in the companion layer,
Henles layer, Huxleys layer and inner root sheath of the hair
follicle. Mutations in K75 predispose to the hair disorder
pseudo-folliculitis barbae. 38. Keratins of Hair Fiber K31 - 40,
K81 - 86. These keartins are expressed within the cuticle and the
cortex of the hair follicle. Mutations in some of these keratins
leads to disorders like monilethrix and ectodermal dysplasia of
hair and nail type. 39. Keratins with unknown expression K23, K24,
K78, K79, K80 These five, very different keratins complete the
family of human keratin proteins. But their expression patterns and
functions are still unknown.
