NPM-ALK fusion dimer binds SKP1:CUL1:RBX1:ZC3HC1

Stable Identifier
R-HSA-9725023
Type
Reaction
Species
Homo sapiens
Compartment
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ZC3HC1, also known as NIPA (nuclear interacting partner of anaplastic lymphoma kinase), was identified as a protein partner of NPM-ALK fusion in two hybrid and co-imuunoprecipitation studies (Ouyang et al, 2003). ZC3HC1 is an F-box component of an SCF complex that targets nuclear CDKN1B (cyclin B1) for ubiquitination and degradation in interphase, regulating mitotic entry (Ouyang et al, 2003; Basserman et al, 2005; Illert et al, 2012). Binding to NPM-ALK depends on ALK kinase activity and is mediated through ZC3HC1 residues 306-402 (Ouyang et al, 2003). ZC3HC1 is predominantly a nuclear protein whose localization is governed by a nuclear localization signal (NLS). Although NPM is a nucleo-cytoplasmic protein, the fusion with ALK does not contain the endogenous NPM NLS, and the fusion is predominantly cytoplasmic. Nuclear localization of the fusion may be mediated by oligomerization with full-length NPM.
ZC3HC1 is phosphorylated downstream of NPM-ALK in a manner that depends on ERK2 (Ouyang et al, 2003; Basserman et al, 2005; Illert et al, 2012; Gegenbacher et al, 2019) Phosphorylation inactivates the SCF complex, allowing CDKN1B to accumulate and drive mitotic entry (Ouyang et al, 2003; Basserman et al, 2005; Illert et al, 2012).

Literature References
PubMed ID Title Journal Year
22955283 Extracellular signal-regulated kinase 2 (ERK2) mediates phosphorylation and inactivation of nuclear interaction partner of anaplastic lymphoma kinase (NIPA) at G2/M

Zech, M, Illert, AL, Duyster, J, Moll, C, Bassermann, F, Peschel, C, Kreutmair, S, Albers, C

J Biol Chem 2012
16009132 NIPA defines an SCF-type mammalian E3 ligase that regulates mitotic entry

Duyster, J, von Klitzing, C, Kawaguchi, H, Morris, SW, Bassermann, F, Bai, RY, Peschel, C, Münch, S

Cell 2005
31434245 Proteomic Phosphosite Analysis Identified Crucial NPM-ALK-Mediated NIPA Serine and Threonine Residues

Dumit, VI, Lippert, LJ, Duyster, J, Müller-Rudorf, A, Illert, AL, Kreutmair, S, Gräßel, L, Poggio, T, Gengenbacher, A

Int J Mol Sci 2019
12748172 Identification and characterization of a nuclear interacting partner of anaplastic lymphoma kinase (NIPA)

Duyster, J, von Klitzing, C, Morris, SW, Bassermann, F, Bai, RY, Peschel, C, Klumpen, S, Miething, C, Ouyang, T

J Biol Chem 2003
Participants
Participates
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Authored
Reviewed
Created
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