There are several pathways of keratinocytes differentiation. Calcium signaling is one
Calcium activates its signaling pathways at least in part via Calcium-sensing receptor
(CASR) , . CASR is a G-protein
alpha-q/11-coupled receptor. It stimulates the hydrolysis of
Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) by
activating Phospholipase C-beta 1 (PLC-beta 1) and
Phospholipase C-gamma 1 (PLC-gamma 1) via v-src sarcoma
viral oncogene homolog (c-Src)
, , . This leads to release of two second
messengers: inositol 1,4,5-trisphosphate
(IP3) and diacylglycerol (DAG).
IP3 then activates IP3 receptor
(IP3R) to release Ca('2+) from
intracellular stores. Ca('2+) and
DAG activates Protein kinase C, alpha
(PKC-alpha), and DAG activates
Protein kinase C, delta (PKC-delta) , , .
1,25-dihydroxycholecalciferol (Calcitriol) plays a
modulatory role in Ca('2+) signaling and promotes
keratinocyte differentiation , .
Calcitriol increases the expression of CASR
and PLC-beta1 and
PLC-gamma1, thus enhancing the sensitivity of the
keratinocyte to Ca('2+)activation , . In addition, Calcitriol induces
Involucrin gene expression via vitamin D receptor
(VDR) pathway .
Activated by Ca('2+)
induces V-raf-1 murine leukemia viral oncogene homolog 1
(c-Raf-1)/ Mitogen-activated protein kinase kinase 1
(MEK1(MAP2K1)), Mitogen-activated protein kinase kinase 2
(MEK2(MAP2K2))/ Mitogen-activated protein kinases 1 and 3
(ERK1/2) signaling that regulates the granular cell stage of
epidermal differentiation by enhancing expression of
Loricrin, Filaggrin, and
Transglutaminase-1 (TGM1) , .
Additionally, PKC-delta can increase
Involicrin gene expression via v-Harvey rat sarcoma viral
oncogene homolog (H-Ras) and several MAPK/MEKK cascades
The first cascade includes Mitogen-activated protein kinase kinase kinase 1
(MEKK1) which phosphorylates Mitogen-activated protein
kinase kinase 3 (MEK3),
thus triggers Mitogen activated protein
kinase 13 (p38delta (MAPK13))
and Mitogen activated protein kinase 14 (p38alpha (MAPK14))
to increase Involucrin gene expression via CCAAT/enhancer
binding protein, alpha (C/EBP alpha) and AP-1 proteins
respectively , .
The second cascade includes mitogen-activated protein kinase kinase 7
(MEK7) and mitogen-activated
protein kinase kinase 6 (MEK6), which are activated by
MEKK1. Then these kinases phosphorylate p38alpha (MAPK14)
and regulate Involucrin promoter activity via AP-1
transcription factors: Jun oncogene(c-Jun),
FBJ murine osteosarcoma viral oncogene homolog
(c-Fos) , , .
By the way, H-Ras/ MEKK1/
Mitogen-activated protein kinase kinase 7 (MEK7)/
Mitogen-activated protein kinase 8 (JNK1) cascade activates
c-Jun, c-Fos and jun D
proto-oncogene (JunD) which
increase expression of
Cystatin A , .
Mitogen-activated protein kinase kinase kinase 5 (ASK1)
signaling pathway is also involved in keratinocyte differentiation. ASK1
Loricrin, and Involucrin via
Mitogen-activated protein kinase kinase 4 (MEK4)/
JNK1 and MEK3/
MEK6/ p38alpha (MAPK14) cascades .
Inhibitor of nuclear factor kappa-B kinase subunit alpha
(IKK-alpha) is also required in keratinocytes
differentiation. In this pathway, TGF-beta1
acts via TGF-beta receptor type I that
phosphorylates and activates 2 SMAD proteins: SMAD family member 3
(SMAD3) and SMAD family member 2
(SMAD2). IKK-alpha interacts
with SMAD2 and SMAD3 that
activates expression of MAX dimerization protein 1 (MAD).
Finally, MAD causes the cessation of cell proliferation
associated with keratinocyte differentiation , .
Notch signaling can trigger two distinct pathways leading to keratinocyte
differentiation. Both Notch homolog 1, translocation-associated (Drosophila)
(Notch1) and Notch homolog 2 (Drosophila)
(Notch2) induce Involucrin gene
expression via Recombination signal binding protein for immunoglobulin kappa J region
(RBP-Jkappa)-independent mechanism leading to keratinocyte
differentiation . In addition, Notch1 can
increase expression another markers of differentiation: Keratin
1 and Keratin 10. This pathway is also
By the way, Notch1-induced
RBP-Jkappa binds to the endogenous Cyclin-dependent kinase inhibitor 1A
(p21) promoter and thus mediates
Notch1-dependent keratinocyte growth arrest and stimulates
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MEK6 regulates human involucrin gene expression via a p38alpha - and p38delta -dependent mechanism.
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