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A p85 isoform switch enhances PI3K activation on endosomes by a MAP4- and PI3P-dependent mechanism.
Thapa, Narendra; Chen, Mo; Cryns, Vincent L; Anderson, Richard.
Afiliación
  • Thapa N; School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA.
  • Chen M; School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA.
  • Cryns VL; Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA.
  • Anderson R; School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA. Electronic address: raanders@wisc.edu.
Cell Rep ; 43(5): 114119, 2024 May 28.
Article en En | MEDLINE | ID: mdl-38630589
ABSTRACT
Phosphatidylinositol 3-kinase α (PI3Kα) is a heterodimer of p110α catalytic and p85 adaptor subunits that is activated by agonist-stimulated receptor tyrosine kinases. Although p85α recruits p110α to activated receptors on membranes, p85α loss, which occurs commonly in cancer, paradoxically promotes agonist-stimulated PI3K/Akt signaling. p110α localizes to microtubules via microtubule-associated protein 4 (MAP4), facilitating its interaction with activated receptor kinases on endosomes to initiate PI3K/Akt signaling. Here, we demonstrate that in response to agonist stimulation and p85α knockdown, the residual p110α, coupled predominantly to p85ß, exhibits enhanced recruitment with receptor tyrosine kinases to endosomes. Moreover, the p110α C2 domain binds PI3-phosphate, and this interaction is also required to recruit p110α to endosomes and for PI3K/Akt signaling. Stable knockdown of p85α, which mimics the reduced p85α levels observed in cancer, enhances cell growth and tumorsphere formation, and these effects are abrogated by MAP4 or p85ß knockdown, underscoring their role in the tumor-promoting activity of p85α loss.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Endosomas / Transducción de Señal / Fosfatos de Fosfatidilinositol / Fosfatidilinositol 3-Quinasa Clase Ia / Proteínas Asociadas a Microtúbulos Límite: Animals / Humans Idioma: En Revista: Cell Rep Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Endosomas / Transducción de Señal / Fosfatos de Fosfatidilinositol / Fosfatidilinositol 3-Quinasa Clase Ia / Proteínas Asociadas a Microtúbulos Límite: Animals / Humans Idioma: En Revista: Cell Rep Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos