Acylpeptide hydrolase is a novel regulator of KRAS plasma membrane localization and function.
J Cell Sci
; 132(15)2019 07 31.
Article
en En
| MEDLINE
| ID: mdl-31266814
ABSTRACT
The primary site for KRAS signaling is the inner leaflet of the plasma membrane (PM). We previously reported that oxanthroquinone G01 (G01) inhibited KRAS PM localization and blocked KRAS signaling. In this study, we identified acylpeptide hydrolase (APEH) as a molecular target of G01. APEH formed a stable complex with biotinylated G01, and the enzymatic activity of APEH was inhibited by G01. APEH knockdown caused profound mislocalization of KRAS and reduced clustering of KRAS that remained PM localized. APEH knockdown also disrupted the PM localization of phosphatidylserine (PtdSer), a lipid critical for KRAS PM binding and clustering. The mislocalization of KRAS was fully rescued by ectopic expression of APEH in knockdown cells. APEH knockdown disrupted the endocytic recycling of epidermal growth factor receptor and transferrin receptor, suggesting that abrogation of recycling endosome function was mechanistically linked to the loss of KRAS and PtdSer from the PM. APEH knockdown abrogated RAS-RAF-MAPK signaling in cells expressing the constitutively active (oncogenic) mutant of KRAS (KRASG12V), and selectively inhibited the proliferation of KRAS-transformed pancreatic cancer cells. Taken together, these results identify APEH as a novel drug target for a potential anti-KRAS therapeutic.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Péptido Hidrolasas
/
Membrana Celular
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Proteínas Proto-Oncogénicas p21(ras)
/
Mutación Missense
/
Sistema de Señalización de MAP Quinasas
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Cell Sci
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos