NPM1-ALK- and PI3K-dependent MDM2 phosphorylation

Stable Identifier
R-HSA-9851102
Type
Reaction [omitted]
Species
Homo sapiens
Compartment
cytosol
ReviewStatus
5/5
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NPM1-ALK- and PI3K-dependent MDM2 phosphorylation
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The TP53 ubiquitin ligase MDM2 is phosphorylated downstream of NPM1-ALK signaling in a manner that depends on the kinase activity of both the fusion protein itself and PI3K (Cui et al, 2009). Inhibition of either ALK or PI3K activity decreases levels of S166 phosphorylated MDM2, enhances MDM2 cytoplasmic localization, and in the case of the PI3K inhibitor LY294002, decreases binding between MDM2 and p53 (Cui et al, 2009). These effects are seen both in primary patient tissues and ALCL cell lines, which contain wild-type TP53 and normal levels of MDM2.
Serine 166 phosphorylation of MDM2 activates the protein and promotes its relocalization to the nucleus, where it ubiquitinates TP53 to promote TP53 degradation (Mayo et al, 2001; Feng et al, 2004; reviewed in Wade et al, 2013). Consistent with this, inhibition of MDM2 activity in NPM1-ALK ALCL cells increases the stability, nuclear localization and activity of TP53, upregulates several TP53 targets, and decreases cellular proliferation (Cui et al, 2009).
Literature References
PubMed ID Title Journal Year
15169778 Stabilization of Mdm2 via decreased ubiquitination is mediated by protein kinase B/Akt-dependent phosphorylation

Feng, J, Tamaskovic, R, Yang, Z, Brazil, DP, Merlo, A, Hess, D, Hemmings, BA

J. Biol. Chem. 2004
23303139 MDM2, MDMX and p53 in oncogenesis and cancer therapy

Wade, M, Li, YC, Wahl, GM

Nat. Rev. Cancer 2013
11504915 A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus

Mayo, LD, Donner, DB

Proc. Natl. Acad. Sci. U.S.A. 2001
19286999 NPM-ALK inhibits the p53 tumor suppressor pathway in an MDM2 and JNK-dependent manner

Cui, YX, Kerby, A, McDuff, FK, Ye, H, Turner, SD

Blood 2009
Participants
Input
Output
Participates
as an event of
This event is regulated
Positively by
Regulator
NPM1(1-117)-p-7Y ALK(1058-1620) fusion dimer:PI3K [cytosol] (Homo sapiens)
Disease
Name Identifier Synonyms
anaplastic large cell lymphoma DOID:0050744
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Cross References
Mondo
Authored
Rothfels, K  (2023-10-14)
Reviewed
Turner, S  (2023-11-08)
Created
Rothfels, K  (2023-10-12)
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