The Biology of Keratinsor

why are they so important?

Birgit Lanebirgit@cmm.a-star.edu.sg

CRUK Cell Structure Research Group, University of Dundee

and

Centre for Molecular Medicine, Singapore

immunofluorescence

“ We live our whole lives less than 1/10mm away from certain death “

W. Montagna

• Tough Tough • Waterproof Waterproof • DisposableDisposable• Self-healingSelf-healing • Site of most cancersSite of most cancers

Skin - the ultimate barrier tissueSkin - the ultimate barrier tissue

K5/K14K5/K14K1/K10K1/K10

EPID

ER

MIS

EPID

ER

MIS

DER

MIS

DER

MIS

QuickTime™ and aCinepak decompressor

are needed to see this picture.

Scratch wound assays

movie: Sharon Jenner

Keratins as Intermediate filament proteins

Cytoskeleton filaments

Many family members

Major structural components of sheet tissues

Different proteins in different body parts

Many diseases (40+)

The Intermediate Filament Gene FamilyThe Intermediate Filament Gene Family

Type IType I keratinskeratins epitheliaepitheliaType IIType II keratinskeratins epitheliaepithelia 54 54Type IIIType III vimentin-likevimentin-like mesenchymemesenchymeType IVType IV neurofilamentsneurofilaments neuronesneuronesType VType V laminslamins all nucleiall nucleiType VIType VI (variable)(variable)____________________________________________________________TotalTotal 7070

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Structure of intermediate filaments

after Herrmann and Aebi

monomer

dimer

tetramer

unit length filament

10 nm filament

immaturefilament

stra

tifi

ed (

bar

rier

)s i

mp

le

Basal cells

Transparent: cornea

Wet: mucosal

Thin dry: cornified (skin)

Stress: fast turnover, wound response

K9- thick dry: palmoplantar skin

Simple: internal,secretory,embryonic

Type II Type I

K2eK2e

K9K9K2pK2p

K10K10

K12K12K3K3

K18K18K8K8

K19K19K14K14K5K5 K15K15

K13K13K4K4

K7K7 K20K20

K16K16K6aK6a

K17K17K6bK6b

K1bK1b

K1K1

bas

alKeratin filament proteins

K5/K14K5/K14

K1/K10K1/K10

EPIDERMIS

EPIDERMIS

DERMIS

DERMIS

Epidermolysis bullosa simplex

stra

tifi

ed (

bar

rier

)s i

mp

le

Basal cells

Transparent: cornea

Wet: mucosal

Thin dry: cornified (skin)

Stress: fast turnover, wound response

K9- thick dry: palmoplantar skin

Simple: internal,secretory,embryonic

Type II Type I

K2eK2e

K9K9K2pK2p

K10K10

K12K12K3K3

K18K18K8K8

K19K19K14K14K5K5 K15K15

K13K13K4K4

K7K7 K20K20

K16K16K6aK6a

K17K17K6bK6b

K1bK1b

K1K1

bas

alKeratin filament proteins

Bullous congenital ichthyosiform erythroderma (BCIE, EHK)

• Thickened skin• Fragile suprabasal cells• Mutations in K1 or K10• Mostly rod end hotspots

stra

tifi

ed (

bar

rier

)s i

mp

le

Basal cells

Transparent: cornea

Wet: mucosal

Thin dry: cornified (skin)

Stress: fast turnover, wound response

K9- thick dry: palmoplantar skin

Simple: internal,secretory,embryonic

Type II Type I

K2eK2e

K9K9K2pK2p

K10K10

K12K12K3K3

K18K18K8K8

K19K19K14K14K5K5 K15K15

K13K13K4K4

K7K7 K20K20

K16K16K6aK6a

K17K17K6bK6b

K1bK1b

K1K1

bas

alKeratin filament proteins

• Fragility late in differentiation• K2e, K1 mutations• Mostly rod end hotspots

Ichthyosis bullosa of Siemens (IBS)

None K5/K14 K1/K10 K2e

Effects of keratin mutations on cell integrity

EBS BCIE (EHK) IBS

stra

tifi

ed (

bar

rier

)s i

mp

le

Basal cells

Transparent: cornea

Wet: mucosal

Thin dry: cornified (skin)

Stress: fast turnover, wound response

K9- thick dry: palmoplantar skin

Simple: internal,secretory,embryonic

Type II Type I

K2eK2e

K9K9K2pK2p

K10K10

K12K12K3K3

K18K18K8K8

K19K19K14K14K5K5 K15K15

K13K13K4K4

K7K7 K20K20

K16K16K6aK6a

K17K17K6bK6b

K1bK1b

K1K1

bas

alKeratin filament proteins

Pachyonychia congenita

- Type 1 (K6a, K16)

- Type 2 (K6b, K17)

K6a/K16, K6b/K17 - the stress response keratins

K6a, K16

- PC-1

K6b, K17

- PC-2

• major keratins in “wet” skin surfaces; outer hair follicle sheath; nail bed.

• NOT normally in thin “dry”skin but more in thick skin

• INDUCED by trauma, wounding• Often expressed in tissue cultured cells

• Small amounts in “wet” epithelia. Lots in deep hair follicle sheath; some basal cells; nail bed. Specialized and unspecialized cells.

• NOT normally in thin “dry” skin.• INDUCED by trauma, wounding, inflammation• Often expressed in tissue cultured cells

K16 induced by epidermal wounding

Healing blister: Keratinocytes downregulate K10 and express K6/K16/K17 upon stress or injury.

+-

K16

epidermis

Outer hair follicle: lots of K16, very little K17

Deep hair follicle: lots of K17, very little K16

Disorders caused by defective intermediate filaments (at least 40 disorders so far)

Skin blistering I, II K5/K14 Hair and nail malformations I, II K6/K16, K6/K17 Thick ridged skin I, II K1/K10 Sloughing white skin in mouth

I, II K4/K13

Corneal surface blisters I, II K3/K12 Thickened palm and sole I, II K9, many other keratins Malformed hair fibres I, II Hair keratins Cysts at hair follicles I, II K6/K17 Pancreatitis II K8 risk factor Liver cirrhosis II K8 risk factor Inflammatory bowel disease II K8 risk factor Myopathies III desmin Muscular dystrophies V A-lamins Cardiomyopathies III, V Desmin, A-lamins Premature ageing V A-lamins lipodystrophy V A-lamins Charcot-Marie-Tooth IV, V Neurofilaments, A-lamins ALS IV, III NF-H, peripherin Alexander disease III GFAP Cataracts VI CP49/phakinin, filensin

http://www.interfil.org