Search results for KERA

Showing 26 results out of 115

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Species

Types

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Protein (3 results from a total of 35)

Identifier: R-HSA-2105019
Species: Homo sapiens
Compartment: lysosomal lumen
Primary external reference: UniProt: KERA: O60938
Identifier: R-HSA-2046150
Species: Homo sapiens
Compartment: Golgi lumen
Primary external reference: UniProt: KERA: O60938
Identifier: R-HSA-2046230
Species: Homo sapiens
Compartment: Golgi lumen
Primary external reference: UniProt: KERA: O60938

Pathway (3 results from a total of 6)

Identifier: R-HSA-1638074
Species: Homo sapiens
Keratan sulfate (KS) (a glycosaminoglycan, GAG) is a linear polysaccharide that consists of the repeating disaccharide unit GlcNAc-Gal (N-acetylglucosamine-galactose). KS can perform a structural function and is found in bone, cartilage and the cornea. In joints, it also acts as a shock absorber due to its highly hydrated nature. There are several classes of KS, KSI, II and III. KSI is N-linked to asparagine (Asn) residues in the core protein and is predominantly found in the cornea. KSII is O-linked to serine (Ser) or Thr (threonine) residues in the core protein and is found predominantly in cartilage linked to the protein aggrecan, forming the most abundant proteoglycan in cartilage. A third class of KS, KSIII, are proteoglycans in the brain. KSIII chains are linked to Ser/Thr residues in the core protein via mannose (Funderburgh 2000, Funderburgh 2002).

Normally, the body degrades GAGs as a natural turnover. Defects in the degradative enzymes cause the autosomal recessive mucopolysaccharide storage disease Morquio's syndrome (also called mucopolysaccharidosis IV). This involves the build up of KS in lysosomes, manifesting clinically as skeletal, dental and corneal abnormalities (Tomatsu et al. 2005).
Identifier: R-HSA-6805567
Species: Homo sapiens
Keratins are the major structural protein of vertebrate epidermis, constituting up to 85% of a fully differentiated keratinocyte (Fuchs 1995). Keratins belong to a superfamily of intermediate filament (IF) proteins that form alpha-helical coiled-coil dimers, which associate laterally and end-to-end to form approximately 10 nm diameter filaments. Keratin filaments are heteropolymeric, formed from equal amounts of acidic type I and basic /neutral type 2 keratins. Humans have 54 keratin genes (Schweitzer et al. 2006). They have highly specific expression patterns, related to the epithelial type and stage of differentiation. Roughly half of human keratins are specific to hair follicles (Langbein & Schweizer 2005). Keratin filaments bundle into tonofilaments that span the cytoplasm and bind to desmosomes and other cell membrane structures (Waschke 2008). This reflects their primary function, maintaining the mechanical stability of individual cells and epithelial tissues (Moll et al. 2008).
Identifier: R-HSA-2022857
Species: Homo sapiens
Keratan sulfate proteoglycans (KSPGs) are degraded in lysosomes as part of normal homeostasis of glycoproteins. Glycoproteins must be completely degraded to avoid undigested fragments building up and causing a variety of lysosomal storage diseases. KSPGs are Asn-linked glycoproteins and are acted upon by exo-glycosidases to release sugar monomers. The main steps of degradation are shown representing the types of cleavage reactions that occur so the full degradation of KS is not shown to avoid repetition. The proteolysis of the core protein of the glycoprotein is not shown here (Winchester 2005, Aronson & Kuranda 1989).

Reaction (3 results from a total of 31)

Identifier: R-HSA-6805546
Species: Homo sapiens
Compartment: cytosol
The first step in keratin assembly is the formation of coiled-coil heterodimers consisting of an acidic type I keratin and a basic or neutral type II keratin (Coulombe & Fuchs 1990, Hatzfeld & Webber 1990, Steinert 1990). In humans, the type I keratins are K9-24, K25-28, which are specific to the inner root sheath of hair, and the hair-specific keratins K31-K38. The type II keratins are K1-8, K71-80 and K81-86 (Bragula & Homberger 2009). Binding between dimer pairs is remarkably strong and can form even in 9M urea (Coulombe & Fuchs 1990). The ~50 nm long middle rod region of keratin protein aligns with its partner in a parallel orientation (Pauling & Corey 1953, Hanukoglu & Fuchs 1983, Parry et al. 1985, Steinert et al. 1994). The rod region is sufficient to form a heterodimer and subsequent tetramers, but the assembly of keratin filaments requires the non-helical head and tail regions (Wilson et al. 1992). The assembly of rod domain heterodimers has asymmetric salt bridges, hydrogen bonds and hydrophobic contacts, and surface of the heterodimer interface exhibits a notable charge polarization (Lee et al. 2012).

In vitro, virtually any type I keratin can dimerize with any type II keratin, leading to the formation of 10-nm long filaments (Franke et al. 1983, Hatzfeld et al. 1987). In vivo, the composition of keratin heterodimers is probably determined by expression. Differing keratin combinations are not characteristic of entire tissues, but probably confer particular functional properties to cells and tissue regions (Bragulla & Homberger 2009). Certain combinations are characteristic of a cell type, e.g. K18/K8 in simple epithelia. At least some keratins can be replaced with no loss of functionality of the keratin filament, e.g. K1/K10, K1/K9, K2/K9, K2/K10 in epithelia (Coulombe & Omary 2002). Suprabasal cells of stratified epithelia express different keratin pairs in different tissues, e.g. skin epidermis predominantly expresses K1/K10, the anterior corneal epithelium produces K3/K12, esophageal epithelium produces K4/K13 (Eichner & Kahn 1990) while hyperproliferative suprabasal cells are characterized by K6/K16 (Sun 2006).
Identifier: R-HSA-9727359
Species: Homo sapiens
Compartment: extracellular region
Spinous keratinocytes form 4-8 layers of cells in the stratum spinosum (spinous layer) of the interfollicular epidermis (reviewed in Fuchs 1990). While spinous layer keratinocytes are considered to be postmitotic (reviewed in Fuchs 1990), they can still be positive for some of the proliferation markers seen in transit amplifying cells, such as MKI67 and histone H3 phosphorylated on serine residue S11. Currently, generic markers of cell proliferation are not annotated in Reactome. The percentage of spinous layer keratinocytes positive for mitotic markers decreases with age and differs between different skin areas (e.g. plantar skin vs. trunk skin) (Nöske et al. 2016). Spinous layer keratinocytes, similar to basal cells of the epidermis, are connected through desmosomes, Ca2+-activated cell cell junctions.

Keratinocytes of the spinosum layer differentiate into keratinocytes of the granulosum layer. Increased Ca2+ concentrations in the upper layer of epidermis induce transcription of granular cell markers, such as LORICRIN (Dlugosz and Yuspa 1993; Hohl et al. 1991) and FLG (filaggrin) (Dlugosz and Yuspa 1993) in a protein kinase C (PKC)-dependent manner. While Ca2+ also stimulates expression of KRT1 and KRT10, activation of PKC leads to rapid inhibition of KRT1 and KRT10 transcription and reduction of KRT1 mRNA stability. Activation of PKC inhibits EGF signaling. PKC-mediated inhibition of KRT1 and KRT10 transcription requires de novo mRNA and protein synthesis. Candidate PKC isoforms that stimulate differentiation of spinous keratinocytes into granular keratinocytes are four PKCs known to be expressed in cultured keratinocytes: PRKCA, PRKCD, PRKCZ, and PRKCH (Dlugosz and Yuspa 1993).

Besides Ca2+, another factor that stimulates differentiation of spinous into granular keratinocytes is hypoxia. Hypoxia leads to HIF1A and EPAS1 (HIF2A)-mediated stimulation of FLG transcription in a Ca2+ independent and cell confluency-independent manner. Hypoxia also stimulates expression of SPINK5, an inhibitor of epidermal serine proteases that regulates conversion of profilaggrin into monomeric filaggrin. Three putative hypoxia response elements (HREs) are found in the promoter region of the human FLG gene, two of which are functional. One of the two functional HREs is evolutionarily conserved. Direct binding of HIF1A/EPAS1 to these HREs has not been demonstrated. Simultaneous HIF1A and EPAS1 deficiency inhibits terminal differentiation of keratinocytes as well as formation of stratum granulosum and cornified envelope but does not affect MKI67 expression in basal layer keratinocytes or KRT10 expression in stratum spinosum (Wong et al. 2015). ARNT (Aryl hydrocarbon receptor nuclear translocator involved in ceramide synthesis) also positively regulates FLG expression without affecting expression of MKI67 in the basal layer or expression of KRT1 and KRT10 in the spinous layer of epidermis (Wong et al. 2015).

Retinoic acid (RA) inhibits transcription of LORICRIN and FLG in granular cells, even in the presence of high Ca2+ (Hohl et al. 1991; Magnaldo et al. 1992) but has little effect on IVL (involucrin) expression (Magnaldo et al. 1992). Critical cell density is also required for accumulation of LORICRIN mRNA (Hohl et al. 1991).

Inhibition of JNK signaling promotes differentiation of keratinocytes and induces the expression of known suprabasal adhesion proteins such as DSC1, DSC3, DSG1, and LY6D (Gazel et al. 2002). LY6D is specifically expressed in keratinocytes from the stratum spinosum at the RNA level, validated by FISH (Cheng et al. 2018) and by in situ sequencing (Ganier et al. 2024).

Markers of keratinocytes of the spinous layer are summarized in the "Table of markers of spinous keratinocytes in interfollicular epidermis". Some of the markers, in particular AQP3 and LGLAS7, are described in more detail in the section "Keratinocyte stem cell differentiates into transit amplifying cell in the basal layer of interfollicular epidermis".

FABP5, epidermal fatty acid binding protein also known as E-FABP, is a terminal differentiation marker expressed in upper layers of stratum spinosum and in stratum granulosum (Le et al. 1998). FABP5 is a lipid carrier, prevalently expressed in postmitotic keratinocytes of stratum spinosum and barely detectable in transit amplifying cells and basal cells; FABP5 may positively regulate KRT10 expression through NFKB and JNK signaling (Dallaglio et al. 2013).

Together with KRT10, KRT1 aggregates into thin bundles called tonofilaments (reviewed in Fuchs et al. 1990). IL4 and IL13 suppress expression of KRT1 and KRT10 in keratinocytes of stratum spinosum in atopic dermatitis (Totsuka et al. 2017).

KRT24 is expressed in upper layers of stratum spinosum and required for Ca2+ induced terminal differentiation of keratinocytes (Min et al. 2017). KRT24 is also expressed in upper layers of stratum spinosum in bioengineered skin (Klar et al. 2018).


Table of markers of spinous keratinocytes in interfollicular epidermis. Please note that keratinocytes in CellMarker database and PanglaoDB correspond to spinous keratinocytes in Reactome.
Marker (protein/RNA)Literature ReferenceCellMarker database – RNA/Protein (Hu et al. 2022)PanglaoDB – RNA (Franzén et al. 2019)
AQP3 (protein)Sugiyama et al. 2001
Ma et al. 2002
Sougrat et al. 2002
NoYes
FAPB5 (protein)Le et al. 1998
Dallaglio et al. 2013
NoNo
KRT1 (protein)reviewed in Fuchs et al. 1990
Totsuka et al. 2017
NoYes
KRT10 (protein)Totsuka et al. 2017NoYes
KRT24 (protein)Min et al. 2017
Klar et al. 2018
LGALS7 (protein)Magnaldo et al. 1995
Umayahara et al. 2020
NoYes
LY6D (RNA)Gazel et al. 2003
Cheng et al. 2018
Ganier et al. 2024
NoNo
Identifier: R-HSA-6806610
Species: Homo sapiens
Compartment: cytosol
Mammalian keratin filaments are produced by the lateral and longitudinal aggregation of subunits, such as tetrameric protofilaments and octameric protofibrils (Aebi et al. 1983). The extent of aggregation depends on the pH and osmolarity of the surrounding cytoplasm (Yamada et al. 2002, Magin et al. 2007). Filaments have a cross-section of 32 keratin molecules (Jones et al. 1997).

Polymer (3 results from a total of 8)

Identifier: R-HSA-446069
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-6809669
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-6809668
Species: Homo sapiens
Compartment: cytosol

Set (3 results from a total of 17)

Identifier: R-HSA-2046203
Species: Homo sapiens
Compartment: Golgi lumen
Identifier: R-HSA-2046314
Species: Homo sapiens
Compartment: Golgi lumen
Identifier: R-HSA-2046206
Species: Homo sapiens
Compartment: Golgi lumen

Complex (3 results from a total of 8)

Identifier: R-HSA-6814735
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-8847733
Species: Homo sapiens
Compartment: cornified envelope
Identifier: R-HSA-6809611
Species: Homo sapiens
Compartment: cytosol

Cell (3 results from a total of 3)

Identifier: R-HSA-9727360
Species: Homo sapiens
Identifier: R-HSA-9727357
Species: Homo sapiens
Identifier: R-HSA-9725559
Species: Homo sapiens

Genes and Transcripts (1 results from a total of 1)

Identifier: R-HSA-1793214
Species: Homo sapiens
Compartment: lysosomal lumen

Chemical Compound (1 results from a total of 1)

Identifier: R-ALL-2299699
Compartment: extracellular region
Primary external reference: ChEBI: keratan sulfate: 60924

Icon (3 results from a total of 5)

Species: Homo sapiens
An epidermal cell which synthesizes keratin and undergoes a characteristic change as it moves upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell.
Species: Homo sapiens
Curator: Bruce May
Designer: Cristoffer Sevilla
Keratin tetramer icon
Keratin tetramer
Species: Homo sapiens
Curator: Bruce May
Designer: Cristoffer Sevilla
Keratin filament icon
A filament composed of acidic and basic keratins (types I and II), typically expressed in epithelial cells
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