3.0
NPM1 in AML
Pathway ID: SIGNOR-AML-NP1
Description: Nucleophosmin (NPM1) is the most frequently mutated gene in Acute Myeloid Leukemia (AML). The protein shows a wide tissue distribution, shuttls between nucleus and cytoplasm, but is mainly localized at nucleoli. NPM1 contains a N-terminal nuclear export signal (NES), a bipartite nuclear localization signal (NLS) and a C-terminal nucleolar localization signal (NoLS). NPM1 mutations in AML are always heterozygous and mutually exclusive with AML carrying recurrent genetic abnormalities. In all instances, the nucleolar localization signal is compromised and a new NES appears. In AML with mutated NPM1, the variant nucleophosmin protein is stably delocalized in the cytoplasm and therefore referred to as NPM1c+ (for cytoplasmic positive). The NPM1c+ protein can bind the wild-type counterpart (through the N-terminal portion) and dominantly delocalize the majority of NPM1 in the cytoplasm. NPM1c+ delocalize in the cytoplasm also its physical interactors, the tumor suppressors p14Arf and Fwb7gamma, causing their degradation, which cause decreased levels of p53 and increased c-Myc half life. Moreover NPM1c+ leads to polyubiquitination and degradation of the tumor suppressor PTEN. PMID: 23436734, 18625840
Curated by: miannu
Description: Nucleophosmin (NPM1) is the most frequently mutated gene in Acute Myeloid Leukemia (AML). The protein shows a wide tissue distribution, shuttls between nucleus and cytoplasm, but is mainly localized at nucleoli. NPM1 contains a N-terminal nuclear export signal (NES), a bipartite nuclear localization signal (NLS) and a C-terminal nucleolar localization signal (NoLS). NPM1 mutations in AML are always heterozygous and mutually exclusive with AML carrying recurrent genetic abnormalities. In all instances, the nucleolar localization signal is compromised and a new NES appears. In AML with mutated NPM1, the variant nucleophosmin protein is stably delocalized in the cytoplasm and therefore referred to as NPM1c+ (for cytoplasmic positive). The NPM1c+ protein can bind the wild-type counterpart (through the N-terminal portion) and dominantly delocalize the majority of NPM1 in the cytoplasm. NPM1c+ delocalize in the cytoplasm also its physical interactors, the tumor suppressors p14Arf and Fwb7gamma, causing their degradation, which cause decreased levels of p53 and increased c-Myc half life. Moreover NPM1c+ leads to polyubiquitination and degradation of the tumor suppressor PTEN. PMID: 23436734, 18625840
Curated by: miannu
