TY - JOUR
T1 - Molecular and functional characterizations of the association and interactions between nucleophosmin-anaplastic lymphoma Kinase and type I Insulin-like growth factor receptor
AU - Shi, Bin
AU - Vishwamitra, Deeksha
AU - Gabrielle Granda, J.
AU - Whitton, Thomas
AU - Shi, Ping
AU - Amin, Hesham M.
N1 - Funding Information:
Abbreviations: ALK, anaplastic lymphoma kinase; CHX, cycloheximide; FBS, fetal bovine serum; GST, glutathione S-transferase; IGF-IR, type I insulin-like growth factor receptor; IP, immunoprecipitation; NPM, nucleophosmin; PDGFR, platelet-derived growth factor receptor; PLA, proximity ligation assay; PLC-γ, phospholipase C–γ; WB, Western blot; WT, wild type Address all correspondence to: Hesham M. Amin, MD, MSc, Department of Hematopathology, Unit 72, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail: hamin@mdanderson.org 1The study is supported by grant R01 CA151533 from the National Cancer Institute and by a Bridge Funding grant from MD Anderson Cancer Center to H.M.A. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The authors declare no competing financial interests. 2This article refers to supplementary materials, which are designated by Figures W1 to W6 and are available online at www.neoplasia.com. Received 3 December 2012; Revised 23 March 2013; Accepted 25 March 2013 Copyright © 2013 Neoplasia Press, Inc. All rights reserved 1522-8002/13/$25.00 DOI 10.1593/neo.122012
PY - 2013
Y1 - 2013
N2 - Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is aberrantly expressed in a subset of T cell lymphoma that commonly affects children and young adults. NPM-ALK possesses significant oncogenic potential that was previously documented using in vitro and in vivo experimental models. The exact mechanisms by which NPM-ALK induces its effects are poorly understood. We have recently demonstrated that NPM-ALK is physically associated with type I insulin-like growth factor receptor (IGF-IR). A positive feedback loop appears to exist between NPM-ALK and IGF-IR through which these two kinases interact to potentiate their effects.We have also found that a single mutation of the Tyr644 or Tyr664 residue of the C terminus of NPM-ALK to phenylalanine decreases significantly, but does not completely abolish, the association between NPM-ALK and IGF-IR. The purpose of this study was to determine whether the dual mutation of Tyr644 and Tyr664 abrogates the association and interactions between NPM-ALK and IGF-IR. We also examined the impact of this dual mutation on the oncogenic potential of NPM-ALK. Our results show that NPMALKY644, 664F completely lacks association with IGF-IR. Importantly, we found that the dual mutation of Tyr644 and Tyr664 diminishes the oncogenic effects of NPM-ALK, including its ability to induce anchorage-independent colony formation and to sustain cellular transformation, proliferation, and migration. Furthermore, the association between NPM-ALK and IGF-IR through Tyr644 and Tyr664 appears to contribute to maintaining the stability of NPM-ALK protein. Our results provide novel insights into the mechanisms by which NPM-ALK induces its oncogenic effects through interactions with IGF-IR in this aggressive lymphoma.
AB - Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is aberrantly expressed in a subset of T cell lymphoma that commonly affects children and young adults. NPM-ALK possesses significant oncogenic potential that was previously documented using in vitro and in vivo experimental models. The exact mechanisms by which NPM-ALK induces its effects are poorly understood. We have recently demonstrated that NPM-ALK is physically associated with type I insulin-like growth factor receptor (IGF-IR). A positive feedback loop appears to exist between NPM-ALK and IGF-IR through which these two kinases interact to potentiate their effects.We have also found that a single mutation of the Tyr644 or Tyr664 residue of the C terminus of NPM-ALK to phenylalanine decreases significantly, but does not completely abolish, the association between NPM-ALK and IGF-IR. The purpose of this study was to determine whether the dual mutation of Tyr644 and Tyr664 abrogates the association and interactions between NPM-ALK and IGF-IR. We also examined the impact of this dual mutation on the oncogenic potential of NPM-ALK. Our results show that NPMALKY644, 664F completely lacks association with IGF-IR. Importantly, we found that the dual mutation of Tyr644 and Tyr664 diminishes the oncogenic effects of NPM-ALK, including its ability to induce anchorage-independent colony formation and to sustain cellular transformation, proliferation, and migration. Furthermore, the association between NPM-ALK and IGF-IR through Tyr644 and Tyr664 appears to contribute to maintaining the stability of NPM-ALK protein. Our results provide novel insights into the mechanisms by which NPM-ALK induces its oncogenic effects through interactions with IGF-IR in this aggressive lymphoma.
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U2 - 10.1593/neo.122012
DO - 10.1593/neo.122012
M3 - Article
C2 - 23730215
AN - SCOPUS:84878652886
SN - 1522-8002
VL - 15
SP - 669
EP - 683
JO - Neoplasia (United States)
JF - Neoplasia (United States)
IS - 6
ER -