TGFß receptor endocytosis and Smad signaling require synaptojanin1, PI3K-C2α-, and INPP4B-mediated phosphoinositide conversions.
Mol Biol Cell
; 31(5): 360-372, 2020 03 01.
Article
em En
| MEDLINE
| ID: mdl-31913757
ABSTRACT
Phosphoinositide conversion regulates a diverse array of dynamic membrane events including endocytosis. However, it is not well understood which enzymes are involved in phosphoinositide conversions for receptor endocytosis. We found by small interfering RNA (siRNA)-mediated knockdown (KD) that class II PI3K α-isoform (PI3K-C2α), the 5'-phosphatase synaptojanin1 (Synj1), and the 4'-phosphatase INPP4B, but not PI3K-C2ß, Synj2, or INPP4A, were required for TGFß-induced endocytosis of TGFß receptor. TGFß induced rapid decreases in PI(4,5)P2 at the plasma membrane (PM) with increases in PI(4)P, followed by increases in PI(3,4)P2, in a TGFß receptor kinase ALK5-dependent manner. TGFß induced the recruitment of both synaptojanin1 and PI3K-C2α to the PM with their substantial colocalization. Knockdown of synaptojanin1 abolished TGFß-induced PI(4,5)P2 decreases and PI(4)P increases. Interestingly, PI3K-C2α KD abolished not only TGFß-induced PI(3,4)P2 increases but also TGFß-induced synaptojanin1 recruitment to the PM, PI(4,5)P2 decreases, and PI(4)P increases. Finally, the phosphoinositide conversions were necessary for TGFß-induced activation of Smad2 and Smad3. These observations demonstrate that the sequential phosphoinositide conversions mediated by Synj1, PI3K-C2α, and INPP4B are essential for TGFß receptor endocytosis and its signaling.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosfatidilinositóis
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Transdução de Sinais
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Receptores de Fatores de Crescimento Transformadores beta
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Monoéster Fosfórico Hidrolases
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Fosfatidilinositol 3-Quinases
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Endocitose
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Proteínas Smad
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Proteínas do Tecido Nervoso
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article