title: Phosphorylation of serine 11 and serine 92 as new positive regulators of human Snail1 function: potential involvement of casein kinase-2 and the cAMP-activated kinase protein kinase A.
abstract: Snail1 is a major factor for epithelial-mesenchymal transition (EMT), an important event in tumor metastasis and in other pathologies. Snail1 is tightly regulated at transcriptional and posttranscriptional levels. Control of Snail1 protein stability and nuclear export by GSK3beta phosphorylation is important for Snail1 functionality. Stabilization mechanisms independent of GSK3beta have also been reported, including interaction with LOXL2 or regulation of the COP9 signalosome by inflammatory signals. To get further insights into the role of Snail1 phosphorylation, we have performed an in-depth analysis of in vivo human Snail1 phosphorylation combined with mutational studies. We identify new phosphorylation sites at serines 11, 82, and 92 and confirmed previously suggested phosphorylations at serine 104 and 107. Serines 11 and 92 participate in the control of Snail1 stability and positively regulate Snail1 repressive function and its interaction with mSin3A corepressor. Furthermore, serines 11 and 92 are required for Snail1-mediated EMT and cell viability, respectively. PKA and CK2 have been characterized as the main kinases responsible for in vitro Snail1 phosphorylation at serine 11 and 92, respectively. These results highlight serines 11 and 92 as new players in Snail1 regulation and suggest the participation of CK2 and PKA in the modulation of Snail1 functionality.
authors.affiliation: Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, Spain.
authors.forename: Matthew Reid
authors.initials: MR
authors.lastname: MacPherson
authors.forename: Patricia
authors.initials: P
authors.lastname: Molina
authors.forename: Serhiy
authors.initials: S
authors.lastname: Souchelnytskyi
authors.forename: Christer
authors.initials: C
authors.lastname: Wernstedt
authors.forename: Jorge
authors.initials: J
authors.lastname: Martin-Pérez
authors.forename: Francisco
authors.initials: F
authors.lastname: Portillo
authors.forename: Amparo
authors.initials: A
authors.lastname: Cano
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015820:Cadherins / Q000235:genetics; D047390:Casein Kinase II / Q000378:metabolism*; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D010748:Phosphopeptides / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D015820:Cadherins; D010748:Phosphopeptides; D012097:Repressor Proteins; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D010768:Phosphoserine; D047390:Casein Kinase II; D017868:Cyclic AMP-Dependent Protein Kinases