Preferred Label : Calcineurin Pathway;
NCIt related terms : Effects of calcineurin in Keratinocyte Differentiation;
Alternative definition : BIOCARTA: The differentiation of keratinocytes constantly replenishes the upper layers
of human skin we lose each day. One factor that contributes to terminal keratinocyte
differentiation is increased levels of intracellular calcium. Adding calcium to the
medium of cultured keratinocytes elevates intracellular calcium and triggers differentiation.
Intracellular calcium levels are also increased in response to phospholipase C activation,
producing IP3 and releasing calcium from stores in the ER. Intracellular calcium alters
multiple signaling pathways, one of which is binding to calmodulin to activate the
serine-threonine protein phosphatase calcineurin. Calcineurin dephosphorylates and
activates the transcription factor NFAT and both calcineurin and NFAT are expressed
in differentiating keratinocytes. Activated NFAT can regulate transcription through
binding its own cognate DNA binding site. One marker of keratinocyte differentiation,
the p21 gene, is activated by NFAT by a different mechanism, with NFAT activating
the p21 promoter by acting as a coactivator for the transcription factors Sp1 and
Sp3.Another protein activated by calcium that may be involved in keratinocyte differentiation
is protein kinase C (PKC). One substrate of activated PKC is MARCKS (myristoylated
alanine-rich kinase C substrate). Phosphorylation of MARCKS by PKC in intact keratinocytes
is not induced during calcium-induced differentiation, but does increase when tested
in vitro. PKC activity is increased by calcium during keratinocyte differentiation
but PKC MARCKS phosphorylation is blocked by the formation of a complex between calmodulin
and MARCKS. The immunosuppressants cyclosporin-A (CsA) and FK506 inhibit T cell activation
through indirect inhibition of NFAT activation and have several side effects including
changes in the skin, suggesting that calcineurin activity may play a role in normal
skin physiology. CsA is used to treat psoriasis, a disease involving abnormal proliferation
of skin cells. The activity of CsA in treating psoriasis may involve inhibition of
immune cells, but may also directly involve inhibition of calcineurin activity in
keratinocytes. (This definition may be outdated - see the DesignNote.);
NCIt note : The BIOCARTA Definition (ALT_DEFINITION) for this pathway concept was provided by
BioCarta. This property was not created by, nor is it maintained by the NCI Thesaurus
staff. Additionally, BioCarta is no longer updating its pathway data; thus, the BIOCARTA
Definition might be outdated or inaccurate. Please see the Terms and Conditions for
Use at http://www.biocarta.com/.;
Biocarta ID : h_calcineurinPathway;
Origin ID : C39010;
UMLS CUI : C1516142;
Semantic type(s)
has_gene_product_element
pathway_has_gene_element