IRSp53 coordinates AMPK and 14-3-3 signaling to regulate filopodia dynamics and directed cell migration.
Mol Biol Cell
; 30(11): 1285-1297, 2019 05 15.
Article
em En
| MEDLINE
| ID: mdl-30893014
ABSTRACT
Filopodia are actin-filled membrane protrusions that play essential roles in cell motility and cell-cell communication and act as precursors of dendritic spines. IRSp53 is an essential regulator of filopodia formation, which couples Rho-GTPase signaling to actin cytoskeleton and membrane remodeling. IRSp53 has three major domains an N-terminal inverse-BAR (I-BAR) domain, a Cdc42- and SH3-binding CRIB-PR domain, and an SH3 domain that binds downstream cytoskeletal effectors. Phosphorylation sites in the region between the CRIB-PR and SH3 domains mediate the binding of 14-3-3. Yet the mechanism by which 14--3-3 regulates filopodia formation and dynamics and its role in cell migration are poorly understood. Here, we show that phosphorylation-dependent inhibition of IRSp53 by 14-3-3 counters activation by Cdc42 and cytoskeletal effectors, resulting in down-regulation of filopodia dynamics and cancer cell migration. In serum-starved cells, increased IRSp53 phosphorylation triggers 14-3-3 binding, which inhibits filopodia formation and dynamics, irrespective of whether IRSp53 is activated by Cdc42 or downstream effectors (Eps8, Ena/VASP). Pharmacological activation or inhibition of AMPK, respectively, increases or decreases the phosphorylation of two of three sites in IRSp53 implicated in 14-3-3 binding. Mutating these phosphorylation sites reverses 14-3-3-dependent inhibition of filopodia dynamics and cancer cell chemotaxis.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Pseudópodes
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Transdução de Sinais
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Movimento Celular
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Processamento de Proteína Pós-Traducional
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Proteína cdc42 de Ligação ao GTP
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Proteínas do Tecido Nervoso
Limite:
Humans
Idioma:
En
Revista:
Mol Biol Cell
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2019
Tipo de documento:
Article