Phosphoproteomics identifies dual-site phosphorylation in an extended basophilic motif regulating FILIP1-mediated degradation of filamin-C.
Amino Acid Motifs
Carrier Proteins
/ metabolism
Cytoskeletal Proteins
/ metabolism
Filamins
/ metabolism
HEK293 Cells
Humans
Muscle Development
Muscle Fibers, Skeletal
/ cytology
Phosphatidylinositol 3-Kinases
/ metabolism
Phosphoproteins
/ metabolism
Phosphorylation
Protein Binding
Proteolysis
Proteome
/ analysis
Proto-Oncogene Proteins c-akt
/ metabolism
Signal Transduction
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
22 05 2020
22 05 2020
Historique:
received:
24
03
2020
accepted:
01
05
2020
entrez:
24
5
2020
pubmed:
24
5
2020
medline:
16
6
2021
Statut:
epublish
Résumé
The PI3K/Akt pathway promotes skeletal muscle growth and myogenic differentiation. Although its importance in skeletal muscle biology is well documented, many of its substrates remain to be identified. We here studied PI3K/Akt signaling in contracting skeletal muscle cells by quantitative phosphoproteomics. We identified the extended basophilic phosphosite motif RxRxxp[S/T]xxp[S/T] in various proteins including filamin-C (FLNc). Importantly, this extended motif, located in a unique insert in Ig-like domain 20 of FLNc, is doubly phosphorylated. The protein kinases responsible for this dual-site phosphorylation are Akt and PKCα. Proximity proteomics and interaction analysis identified filamin A-interacting protein 1 (FILIP1) as direct FLNc binding partner. FILIP1 binding induces filamin degradation, thereby negatively regulating its function. Here, dual-site phosphorylation of FLNc not only reduces FILIP1 binding, providing a mechanism to shield FLNc from FILIP1-mediated degradation, but also enables fast dynamics of FLNc necessary for its function as signaling adaptor in cross-striated muscle cells.
Identifiants
pubmed: 32444788
doi: 10.1038/s42003-020-0982-5
pii: 10.1038/s42003-020-0982-5
pmc: PMC7244511
doi:
Substances chimiques
Carrier Proteins
0
Cytoskeletal Proteins
0
FILIP1 protein, human
0
FLNC protein, human
0
Filamins
0
Phosphoproteins
0
Proteome
0
AKT1 protein, human
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
253Subventions
Organisme : Wellcome Trust
ID : 201543/Z/16
Pays : United Kingdom
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