Pathway: Formation of the cornified envelope
Reactions in pathway: Formation of the cornified envelope :
Formation of the cornified envelope
As keratinocytes progress towards the upper epidermis, they undergo a unique process of cell death termed cornification (Eckhart et al. 2013). This involves the crosslinking of keratinocyte proteins such as loricrin and involucrin by transglutaminases and the breakdown of the nucleus and other organelles by intracellular and secreted proteases (Eckhart et al. 2000, Denecker et al. 2008). This process is strictly regulated by the Ca2+ concentration gradient in the epidermis (Esholtz et al. 2014). Loricrin and involucrin are encoded in ‘Epidermal Differentiation Complex’ linked to a large number of genes encoding nonredundant components of the CE (Kypriotou et al. 2012, Niehues et al. 2016). Keratinocytes produce specialized proteins and lipids which are used to construct the cornified envelope (CE), a heavily crosslinked submembranous layer that confers rigidity to the upper epidermis, allows keratin filaments to attach to any location in the cell membrane (Kirfel et al. 2003) and acts as a water-impermeable barrier. The CE has two functional parts: covalently cross-linked proteins (10 nm thick) that comprise the backbone of the envelope and covalently linked lipids (5 nm thick) that coat the exterior (Eckert et al. 2005). Desmosomal components are crosslinked to the CE to form corneodesmosomes, which bind cornified cells together (Ishida-Yamamoto et al. 2011). Mature terminally differentiated cornified cells consist mostly of keratin filaments covalently attached to the CE embedded in lipid lamellae (Kalinin et al. 2002). The exact composition of the cornified envelope varies between epithelia (Steinert et al. 1998); the relative amino-acid composition of the proteins used may determine differential mechanical properties (Kartasova et al. 1996).
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).
As early steps towards capturing the array of processes by which a fertilized egg gives rise to the diverse tissues of the body, examples of several processes have been annotated. Aspects of processes involved in most developmental processes, transcriptional regulation of pluripotent stem cells, gastrulation, and activation of HOX genes during differentiation are annotated. More specialized processes include nervous system development , aspects of the roles of cell adhesion molecules in axonal guidance and myogenesis, transcriptional regulation in pancreatic beta cell, cardiogenesis, transcriptional regulation of granulopoeisis, transcriptional regulation of testis differentiation, transcriptional regulation of white adipocyte differentiation, and molecular events of "nodal" signaling, LGI-ADAM interactions, and keratinization.