title: The Ca2+-dependent protease Calpain A regulates Cactus/I kappaB levels during Drosophila development in response to maternal Dpp signals.
abstract: Regulation of NF kappaB activity is central to many processes during development and disease. Activation of NF kappaB family members depends on degradation of inhibitory I kappaB proteins. In Drosophila, a nuclear gradient of the NF kappaB/c-rel protein Dorsal subdivides the embryonic dorsal-ventral axis, defining the extent and location of mesodermal and ectodermal territories. Activation of the Toll pathway directs Dorsal nuclear translocation by inducing proteosomal degradation of the I kappaB homologue Cactus. Another mechanism that impacts on Dorsal activation involves the Toll-independent pathway, which regulates constitutive Cactus degradation. We have shown that the BMP protein Decapentaplegic (Dpp) inhibits Cactus degradation independent of Toll. Here we report on a novel element of this pathway: the calcium-dependent protease Calpain A. Calpain A knockdowns increase Cactus levels, shifting the Dorsal gradient and dorsal-ventral patterning. As shown for mammalian I kappaB, this effect requires PEST sequences in the Cactus C-terminus, implying a conserved role for calpains. Alteration of Calpain A or dpp results in similar effects on Dorsal target genes. Epistatic analysis confirms Calpain A activity is regulated by Dpp, indicating that Dpp signals increase Cactus levels through Calpain A inhibition, thereby interfering with Dorsal activation. This mechanism may allow coordination of Toll, BMP and Ca(2+) signals, conferring precision to Dorsal-target expression domains.
authors.affiliation: Institute for Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: M
authors.initials: M
authors.lastname: Fontenele
authors.forename: K
authors.initials: K
authors.lastname: Carneiro
authors.forename: R
authors.initials: R
authors.lastname: Agrellos
authors.forename: D
authors.initials: D
authors.lastname: Oliveira
authors.forename: A
authors.initials: A
authors.lastname: Oliveira-Silva
authors.forename: V
authors.initials: V
authors.lastname: Vieira
authors.forename: E
authors.initials: E
authors.lastname: Negreiros
authors.forename: E
authors.initials: E
authors.lastname: Machado
authors.forename: H
authors.initials: H
authors.lastname: Araujo
mesh_terms: D000818:Animals; D002118:Calcium / Q000737:chemistry*; D002154:Calpain / Q000737:chemistry*; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000502:physiology; D004330:Drosophila / Q000196:embryology*; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000502:physiology*; D004331:Drosophila melanogaster; D018507:Gene Expression Regulation, Developmental; D020672:I-kappa B Proteins / Q000378:metabolism*; D008954:Models, Biological; D010641:Phenotype; D010750:Phosphoproteins / Q000096:biosynthesis / Q000502:physiology; D012330:RNA, Double-Stranded / Q000737:chemistry; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D020672:I-kappa B Proteins; D010750:Phosphoproteins; D012330:RNA, Double-Stranded; D051193:Toll-Like Receptors; C064196:dpp protein, Drosophila; C077938:cact protein, Drosophila; D002154:Calpain; D002118:Calcium