Transient activation of FOXN1 in keratinocytes induces a transcriptional programme that promotes terminal differentiation: contrasting roles of FOXN1 and Akt

Janes, Sam M.; Ofstad, Tyler; Campbell, Douglas Houghton; Watt, Fiona M.; Prowse, David M.

doi:10.1242/jcs.01302

Cited by 83 publications

(106 citation statements)

References 59 publications

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“…We infer that the fetal, parabasal pulse of Akt activity is equivalent to that reported in cultured keratinocytes because (i) it reappears in organotypic cultures (this work; Ref. 16) and (ii) it associates with early differentiation in cultured keratinocytes (17,18) where it has been linked to keratinocyte differentiation and survival. In adult skin it is likely that this lower form is still present, although the lower levels are usually below or just bordering the limits of detection histologically.…”

Section: Discussionsupporting

confidence: 64%

AKT-dependent HspB1 (Hsp27) Activity in Epidermal Differentiation

O'Shaughnessy

Welti

Cooke

et al. 2007

Journal of Biological Chemistry

117

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AKT activity has been reported in the epidermis associated with keratinocyte survival and differentiation. We show in developing skin that Akt activity associates first with post-proliferative, para-basal keratinocytes and later with terminally differentiated keratinocytes that are forming the fetal stratum corneum. In adult epidermis the dominant Akt activity is in these highly differentiated granular keratinocytes, involved in stratum corneum assembly. Stratum corneum is crucial for protective barrier activity, and its formation involves complex and poorly understood processes such as nuclear dissolution, keratin filament aggregation, and assembly of a multiprotein cell cornified envelope. A key protein in these processes is filaggrin. We show that one target of Akt in granular keratinocytes is HspB1 (heat shock protein 27). Loss of epidermal HspB1 caused hyperkeratinization and misprocessing of filaggrin. Akt-mediated HspB1 phosphorylation promotes a transient interaction with filaggrin and intracellular redistribution of HspB1. This is the first demonstration of a specific interaction between HspB1 and a stratum corneum protein and indicates that HspB1 has chaperone activity during stratum corneum formation. This work demonstrates a new role for Akt in epidermis.The epidermis is the primary environmental barrier, protecting from infection, allergens, and damage from UV radiation. The major constituent of this epidermal barrier is the terminally differentiated, anuclear keratinocyte. This structure is bounded by a cornified envelope, an elaborate, cross-linked protein structure covalently bound to hydrophobic lipid externally and aggregated keratin internally (1). Formation of this structure is poorly understood.The complexity of keratinocyte terminal differentiation and the importance of precisely timed and compartmentalized processing is illustrated by the maturation of the stratum corneum protein filaggrin. Filaggrin is synthesized as a high molecular mass precursor comprising multiple subunits that are sequentially processed and modified in temporally and spatially regulated steps by diverse proteases and enzymes to produce mature filaggrin subunits. Mature filaggrin is thought to be important in the aggregation and collapse of the keratin network leading to flattening of the keratinocyte and the destruction of the nucleus in granular layer (terminally differentiating) keratinocytes (2). Filaggrin is also incorporated into the cornified envelope (2). Premature or aberrant filaggrin processing can be catastrophic, leading to disruption of cornified envelope integrity and skin barrier function (3-5) and is far more damaging than reduced filaggrin levels that, in contrast, lead only to mild skin defects (6).Possible regulators of protein processing and trafficking during terminal differentiation are heat shock proteins (Hsps). 2Hsps have diverse roles as cellular chaperones, anti-apoptotic factors, stress-protective proteins, and cytoskeletal stabilizers (7,8). Human HspB1 (Hsp27) (9 -11) and the mouse HspB1...

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Section: Discussionsupporting

confidence: 64%

AKT-dependent HspB1 (Hsp27) Activity in Epidermal Differentiation

O'Shaughnessy

Welti

Cooke

et al. 2007

Journal of Biological Chemistry

117

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“…However, although Akt1 nulls have defective cornified envelopes (O'Shaughnessy et al, 2007b), both Akt1 and Akt2 knockouts are viable, suggesting a degree of redundancy between these Akt proteins. Phosphorylated active Akt is found in two regions of the epidermis -the lower suprabasal epidermis and the upper granular layer (Janes et al, 2004;O'Shaughnessy et al, 2007b). Our previous work has determined that this lower suprabasal activity mostly comprises Akt2, whereas the upper granular layer activity mostly comprises Akt1 (O'Shaughnessy et al, 2007a;O'Shaughnessy et al, 2007b).…”

Section: Introductionmentioning

confidence: 96%

“…Akt activity is also present in cultured keratinocytes, probably corresponding to the lower suprabasal activity (Janes et al, 2004;Calautti et al, 2005;Thrash et al, 2006;O'Shaughnessy et al, 2007b). Multiple roles have been proposed for epidermal Akt, from the initiation of the terminal differentiation program (Janes et al, 2004;Calautti et al, 2005;Thrash et al, 2006;O'Shaughnessy et al, 2007b;Janes et al, 2009) to the correct formation of the cornified envelope during late terminal differentiation, partly by regulating filaggrin processing (O'Shaughnessy et al, 2007a;O'Shaughnessy et al, 2007b).…”

Section: Introductionmentioning

confidence: 99%

Akt-dependent Pp2a activity is required for epidermal barrier formation during late embryonic development

O'Shaughnessy

Welti²,

Sully³

et al. 2009

Development

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Acquisition of epidermal barrier function occurs late in mouse gestation. Several days before birth a wave of barrier acquisition sweeps across murine fetal skin, converging on dorsal and ventral midlines. We investigated the molecular pathways active during epidermal barrier formation. Akt signaling increased as the barrier wave crossed epidermis and Jun was transiently dephosphorylated. Inhibitor experiments on embryonic explants showed that the dephosphorylation of Jun was dependent on both Akt and protein phosphatase 2A(Pp2a). Inhibition of Pp2a and Akt signaling also caused defects in epidermal barrier formation. These data are compatible with a model for developmental barrier acquisition mediated by Pp2a regulation of Jun dephosphorylation,downstream of Akt signaling. Support for this model was provided by siRNA-mediated knockdown of Ppp2r2a (Pr55α or B55α), a regulatory subunit of Pp2a expressed in an Akt-dependent manner in epidermis during barrier formation. Ppp2r2a reduction caused significant increase in Jun phosphorylation and interfered with the acquisition of barrier function, with barrier acquisition being restored by inhibition of Jun phosphorylation. Our data provide strong evidence that Ppp2r2a is a regulatory subunit of Pp2a that targets this phosphatase to Jun, and that Pp2a action is necessary for barrier formation. We therefore describe a novel Akt-dependent Pp2a activity that acts at least partly through Jun to affect initial barrier formation during late embryonic epidermal development.

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“…Activation of the serine/threonine kinase AKT/ PKB positively impacts on three cellular processes relevant to tumor progression: proliferation/differentiation, survival and cell size/growth. Inhibition of AKT can prolong the lifespan of primary cultured human endothelial cells (Janes et al, 2004), whereas constitutive activation of AKT can foster senescence-like growth arrest via a p53/p21-dependent pathway and inhibition of FOXO3a transcription (Janes et al, 2004). AKT-induced growth arrest was inhibited by a mutated forkhead transcription factor that was resistant to AKT-mediated phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

AKT induces senescence in primary esophageal epithelial cells but is permissive for differentiation as revealed in organotypic culture

et al. 2006

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Epidermal growth factor receptor (EGFR) overexpression and activation is critical in the initiation and progression of cancers, especially those of epithelial origin. EGFR activation is associated with the induction of divergent signal transduction pathways and a gamut of cellular processes; however, the cell-type and tissue-type specificity conferred by certain pathways remains to be elucidated. In the context of the esophageal epithelium, a prototype stratified squamous epithelium, EGFR overexpression is relevant in the earliest events of carcinogenesis as modeled in a three-dimensional organotypic culture system. We demonstrate that the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, and not the MEK/MAPK (mitogen-activated protein kinase) pathway, is preferentially activated in EGFR-mediated esophageal epithelial hyperplasia, a premalignant lesion. The hyperplasia was abolished with direct inhibition of PI3K and of AKT but not with inhibition of the MAPK pathway. With the introduction of an inducible AKT vector in both primary and immortalized esophageal epithelial cells, we find that AKT overexpression and activation is permissive for complete epithelial formation in organotypic culture, but imposes a growth constraint in cells grown in monolayer. In organotypic culture, AKT mediates changes related to cell shape and size with an expansion of the differentiated compartment.

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Transient activation of FOXN1 in keratinocytes induces a transcriptional programme that promotes terminal differentiation: contrasting roles of FOXN1 and Akt

Cited by 83 publications

References 59 publications

AKT-dependent HspB1 (Hsp27) Activity in Epidermal Differentiation

AKT-dependent HspB1 (Hsp27) Activity in Epidermal Differentiation

Akt-dependent Pp2a activity is required for epidermal barrier formation during late embryonic development

AKT induces senescence in primary esophageal epithelial cells but is permissive for differentiation as revealed in organotypic culture

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