Multiple roles for keratin intermediate filaments in the regulation of epithelial barrier function and apico-basal polarity

Figures & data

Table 1. Keratin expression in tissues described in this review.

Epithelium	Cell type	Type I	Type II	References
Simple	Hepatocytes	K18	K8	^12
	Intestine crypt	K18 K19 K20 K23	K8 K7	^131
	Intestine villus	K18 K19 K20	K8	^95
	Pancreatic ducts	K18 K19	K4 K8 K7	^132
Stratified	Epidermis basal	K14 K15 K17	K5 K6	^11
	Epidermis suprabasal / spinous	K16 K10	K6 K1 K2^*	^11
	Mammary  gland duct	K14 K17 K18 K19	K5 K7 K8	^11

Note.

* Epidermis spinous/granular

Table 2. Examples of effects of changes in keratin expression or keratin mutations on signaling pathways.

Affected keratin(s)	Effects	Ref.
K19 knockdown	Enhanced Akt signaling (decreased PTEN)	^133
K19 knockdown	Destabilization of HER2 / decreased ERK	^134
K5 and 14 mutations	Epidermolysis bullosa simplex (EBS) rescued by ERK inhibition	^135
K17 overexpression	Activates Akt signaling in Ewing sarcoma	^136
K17 overexpression	Activation of transcriptional regulator AIRE	^106,137
K17 knockdown	Decreased pTyr-23 annexin A2	^138
K14 knockdown (and decreased partner K5)	Decreased pAkt and enhanced Notch1	^139
K14 overexpression	Increased JNK-MAPK signals	^22
K8/K18 or K8/K19 overexpression	Raf-1 is released from 14-3-3 by stress	^80
K8 null hepatocytes	Fas-activated apoptosis mediated by DEDD	^140
K8 null hepatocytes	Inactive p38 MAPK, p44/42 MAPK and JNK1/2 are released from IF upon activation during apoptosis	^141
K8 knockdown	Increased PI3K/Akt activation	^142
K8 knockdown	Protein kinase C, cell adhesion and migration	^45
K8 null mouse and K8 knockdown	Post-translational downregulation of aPKC via Hsp/Hsc70	^33,52
K18 knockdown	MacroD1 (LRP16) retention in the cytoplasm	^143
K17 knockout	Increased TNFR – NF-kB activity through TRADD	^31
Global type I or II keratin knockout: rescue by expression of K6/K17 or K5/K14	Increased PKCα activity, desmosome destabilization	^92
Global type II keratin knockout	GLUT1 – 3 mislocalization, AMPK and mTOR activation	^113
Global type II keratin knockout	Increased EGFR and PKCα-dependent Erk1/2 signaling	^112
Global type II keratin knockout	Rack1-keratin interactions modulate PKC-α signaling	^144

Note. Bolded protein names indicate evidence for binding to keratin IF (scaffolding). Knockdown refers to RNAi manipulation in cell lines. Overexpression indicates vector-mediated transcription in cell lines.

Table 3. Examples of effects of keratin loss or keratin mutations on inflammatory mechanisms.

Affected keratin(s)	Effects	Ref.
K16 knockout	Regulates innate immunity in response to epithelial barrier opening	^99
R156H K10 overexpression	Activation of p38, secretion of TNFα and RANTES	^109
K17 knockout	Polarizes immune response, Th2 cytokine profile	^145
K5 knockout	Transcriptional  upregulation of pro-inflammatory cytokines IL-6 and IL-1β	^108
K8 knockout	Th2 chronic intestinal inflammation	^96
K8 / 18 mutations	Intestinal cell barrier function	^98
K8 / 18 knockdown	Activates NF-kB in cancer cells	^142
K10 expression in basal layer of epidermis	Decreased NF-kB activity	^100

Figure 1. Polarity of IF in simple epithelia. A, B Frozen sections of formaldehyde-fixed liver (A) and small intestine epithelium (B) stained with anti-K8 antibody (red) and DAPI (light blue). Bar, 20 µm.

Figure 2. Polarized scaffolding of Hsp/Hsc70 in simple epithelia. Frozen sections of villus enterocytes from K8-null or heterozygous littermates were immunostained for K8 (red channel) or Hsp/Hsc70 (green channel). The arrow points at the apical concentration of the chaperone which is strictly dependent on the expression of keratin IF. Modified from.⁵² Bar, 20 µm.

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