溶酶体
细胞生物学
组织蛋白酶B
入侵足纲
胰腺癌
生物
组织蛋白酶
癌细胞
癌症研究
癌症
生物化学
遗传学
酶
作者
Omar L. Gutierrez-Ruiz,Katherine M. Johnson,Eugene W. Krueger,Roseanne E. Nooren,Nicole Cruz-Reyes,Carrie J. Heppelmann,Tara L. Hogenson,Martín E. Fernández-Zapico,Mark A. McNiven,Gina L. Razidlo
出处
期刊:Cell Reports
[Elsevier]
日期:2023-09-01
卷期号:42 (9): 113042-113042
标识
DOI:10.1016/j.celrep.2023.113042
摘要
Amplified lysosome activity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) orchestrated by oncogenic KRAS that mediates tumor growth and metastasis, though the mechanisms underlying this phenomenon remain unclear. Using comparative proteomics, we found that oncogenic KRAS significantly enriches levels of the guanine nucleotide exchange factor (GEF) dedicator of cytokinesis 8 (DOCK8) on lysosomes. Surprisingly, DOCK8 is aberrantly expressed in a subset of PDAC, where it promotes cell invasion in vitro and in vivo. DOCK8 associates with lysosomes and regulates lysosomal morphology and motility, with loss of DOCK8 leading to increased lysosome size. DOCK8 promotes actin polymerization at the surface of lysosomes while also increasing the proteolytic activity of the lysosomal protease cathepsin B. Critically, depletion of DOCK8 significantly reduces cathepsin-dependent extracellular matrix degradation and impairs the invasive capacity of PDAC cells. These findings implicate ectopic expression of DOCK8 as a key driver of KRAS-driven lysosomal regulation and invasion in pancreatic cancer cells.
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