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

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2019 Aug 23

PMID 31434245

Citations 4

Authors

Anina Gengenbacher

Alina Muller-Rudorf

Teresa Poggio

Linda Grassel

Veronica I Dumit

Stefanie Kreutmair

Lena J Lippert

Justus Duyster

Anna L Illert

Affiliations

Soon will be listed here.

Abstract

Anaplastic large-cell lymphoma (ALCL) is an aggressive non-Hodgkin lymphoma that shows in 60% of cases a translocation t(2;5)(p23;q35), which leads to the expression of the oncogenic kinase NPM-ALK. The nuclear interaction partner of ALK (NIPA) defines an E3-SCF ligase that contributes to the timing of mitotic entry. It has been shown that co-expression of NIPA and NPM-ALK results in constitutive NIPA phosphorylation. By mass spectrometry-based proteomics we identified nine serine/threonine residues to be significantly upregulated in NIPA upon NPM-ALK expression. Generation of phospho-deficient mutants of the respective phospho-residues specified five serine/threonine residues (Ser-338, Ser-344, Ser-370, Ser-381 and Thr-387) as key phosphorylation sites involved in NPM-ALK-directed phosphorylation of NIPA. Analysis of the biological impact of NIPA phosphorylation by NPM-ALK demonstrated that the ALK-induced phosphorylation does not change the SCF-complex formation but may influence the localization of NIPA and NPM-ALK. Biochemical analyses with phospho-deficient mutants elucidated the importance of NIPA phosphorylation by NPM-ALK for the interaction of the two proteins and proliferation potential of respective cells: Silencing of the five crucial NIPA serine/threonine residues led to a highly enhanced NIPA-NPM-ALK binding capacity as well as a slightly reduced proliferation in Ba/F3 cells.

Citing Articles

NIPA (Nuclear Interaction Partner of ALK) Is Crucial for Effective NPM-ALK Mediated Lymphomagenesis.

Kreutmair S, Lippert L, Klingeberg C, Albers-Leischner C, Yacob S, Shlyakhto V Front Oncol. 2022; 12:875117.

PMID: 35646639 PMC: 9137267. DOI: 10.3389/fonc.2022.875117.

ZC3HC1 is a structural element of the nuclear basket effecting interlinkage of TPR polypeptides.

Gunkel P, Cordes V Mol Biol Cell. 2022; 33(9):ar82.

PMID: 35609216 PMC: 9582634. DOI: 10.1091/mbc.E22-02-0037.

ZC3HC1 Is a Novel Inherent Component of the Nuclear Basket, Resident in a State of Reciprocal Dependence with TPR.

Gunkel P, Iino H, Krull S, Cordes V Cells. 2021; 10(8).

PMID: 34440706 PMC: 8393659. DOI: 10.3390/cells10081937.

Current Methods of Post-Translational Modification Analysis and Their Applications in Blood Cancers.

Dunphy K, Dowling P, Bazou D, OGorman P Cancers (Basel). 2021; 13(8).

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