Translating genetic, biochemical and structural information to the calpain view of development

Abstract

Embryonic development repeatedly deploys a finite number of signaling pathways to control a multitude of processes such as patterning, growth and differentiation. Diversity in gene expression resulting from these signals depends on the epigenetic landscape as well as the network of interactions between different pathways at a given time. A third mechanism to generate diversity from a sole signal is to modify downstream pathway effectors by modulatory protein activity. The calcium-dependent calpain proteases are modulatory proteases that cleave proteins at specific sites, generating fragments, or neoproteins, with novel functions. Among calpain substrates are effectors of the Wnt and NFκB pathways, ERK pathway and ionic channel receptors, and cell cycle regulators. Loss of calpain function is associated to muscular dystrophy, deterioration of neural connections and embryonic patterning defects. Here we review the basic features of calpains, the principles that guide regulation by calpain activity, and recent literature on how calpain function controls fundamental aspects of animal development.

Deletion of the Capn1 Gene Results in Alterations in Signaling Pathways Related to Alzheimer’s Disease, Protein Quality Control and Synaptic Plasticity in Mouse Brain

“…Additionally, changes in some of these DGEs may also be due to compensational responses. A recent review discusses the roles of calpain during development and although it indicates that calpain plays a role in various aspects of development, including cell division and cell migration, our understanding on its overall function remains very limited (Araujo et al, 2018).…”

Calpain DEK1 acts as a developmental switch gatekeeping cell fate transitions

“…The functional roles in the regulation of cell division and the cell cycle seems to be the ancestral state of the entire superfamily (Zhao et al, 2012;Vieira et al, 2017). Consistent with the broad functional importance of the calpain system as well as the pleiotropy and severity of loss of function mutants in various eukaryotic model systems, human calpains have been found as aggravating factors in many pathophysiological conditions and illnesses including various cancers and hereditary diseases like muscular dystrophy (Storr et al, 2011;Ono and Sorimachi, 2012;Ono et al, 2016;Araujo et al, 2018).…”

“…Like classical calpains, the full DEK1 protein demonstrates autoproteolytic activity releasing several soluble neo-proteins with cytosolic localization (Johnson et al, 2008). The membrane-localized full-length protein thus likely represents the inactive calpain that might be activated by phosphorylation (Moody, 2019), mechanosensing (Tran et al, 2017) or other sources emitting local Ca 2+ pulses similar to the classical calpains (Araujo et a., 2018). All of this, taken together with the phylogeny, phenotypic data and the observed broad functionality that is expressed by conserved functions in basic biological processes and convergently evolved roles in development, points to a deep conservation of the CysPc-C2L protease domain's molecular function.…”

A reaction-diffusion network model predicts a dual role of Cactus/IκB to regulate Dorsal/NFκB nuclear translocation in Drosophila

“…However, several reports indicate that the signal-independent pathway is regulated by Casein kinase II [ 20 , 23 ], the BMP protein encoded by decapentaplegic [ 24 , 25 ] and by the calcium-dependent modulatory protease Calpain A [ 26 ]. Moreover, Calpain A generates a Cact fragment that is more stable than full-length Cact [ 17 , 27 ], indicating that the Toll-independent pathway may perform unexplored roles in nDl gradient formation. Free Cact seems to be the preferential target for this Toll independent pathway, since at least one of its elements, namely Calpain A, has no effect on Cact that is complexed to Dl [ 17 ].…”