Development - Keratinocyte differentiation

Keratinocyte differentiation

There are several pathways of keratinocytes differentiation. Calcium signaling is one of them.

Calcium activates its signaling pathways at least in part via Calcium-sensing receptor (CASR) [1], [2]. 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) [3], [4], [5]. 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) [5], [6], [7].

1,25-dihydroxycholecalciferol (Calcitriol) plays a modulatory role in Ca('2+) signaling and promotes keratinocyte differentiation [8], [9]. Calcitriol increases the expression of CASR and PLC-beta1 and PLC-gamma1, thus enhancing the sensitivity of the keratinocyte to Ca('2+)activation [8], [10]. In addition, Calcitriol induces Involucrin gene expression via vitamin D receptor (VDR) pathway [5].

Activated by Ca('2+) PKC-alpha 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) [6], [11].

Additionally, PKC-delta can increase Involicrin gene expression via v-Harvey rat sarcoma viral oncogene homolog (H-Ras) and several MAPK/MEKK cascades [7], [12].

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 [13], [14].

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) [13], [15], [16].

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 [17], [18].

Mitogen-activated protein kinase kinase kinase 5 (ASK1) signaling pathway is also involved in keratinocyte differentiation. ASK1 activates TGM1, Loricrin, and Involucrin via Mitogen-activated protein kinase kinase 4 (MEK4)/ JNK1 and MEK3/ MEK6/ p38alpha (MAPK14) cascades [19].

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 [20], [21].

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 [22]. In addition, Notch1 can increase expression another markers of differentiation: Keratin 1 and Keratin 10. This pathway is also RBP-Jkappa-independent. [22].

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 differentiation [23].

References:

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