title: Molecular and functional characterizations of the association and interactions between nucleophosmin-anaplastic lymphoma kinase and type I insulin-like growth factor receptor.
abstract: 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 Tyr(644) or Tyr(664) 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 Tyr(644) and Tyr(664) 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 NPM-ALK(Y644,664F) completely lacks association with IGF-IR. Importantly, we found that the dual mutation of Tyr(644) and Tyr(664) 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 Tyr(644) and Tyr(664) 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.
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Shi
authors.forename: Deeksha
authors.initials: D
authors.lastname: Vishwamitra
authors.forename: J Gabrielle
authors.initials: JG
authors.lastname: Granda
authors.forename: Thomas
authors.initials: T
authors.lastname: Whitton
authors.forename: Ping
authors.initials: P
authors.lastname: Shi
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Amin
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D006801:Humans; D000068877:Imatinib Mesylate; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells / Q000187:drug effects; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D055550:Protein Stability; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D014443:Tyrosine / Q000235:genetics
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D014443:Tyrosine; D000068877:Imatinib Mesylate; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D020797:Receptor, Platelet-Derived Growth Factor beta; D051966:Phospholipase C gamma