Nucleophosmin-anaplastic lymphoma kinase of anaplastic large-cell lymphoma recruits, activates, and uses pp60c-src to mediate its mitogenicity.
Anaplastic large-cell lymphomas (ALCLs) are lymphomas of T or null phenotype often associated with a chromosomal translocation, t(2;5)(p23;q35). This translocation leads to the expression of a hybrid protein consisting of the N-terminal portion of nucleophosmin (NPM) and the intracellular domain of the anaplastic lymphoma kinase (ALK). NPM-ALK possesses a constitutive tyrosine kinase activity responsible for its oncogenic property through activation of downstream effectors such as phospholipase C gamma (PLC-gamma) and the type IA phosphoinositide 3-kinase. Here, we show that the Src-kinases, particularly pp60(c-src), associate with and are activated by NPM-ALK expression in various cells, and in cell lines established from patients with ALCL. The kinase activity and the tyrosine 418 of NPM-ALK are required for its association with Src-kinases. Y418F mutation of NPM-ALK impaired its association with Src-kinases and strongly reduced the proliferation rate of Ba/F3 cells. In agreement, Src-kinase inhibitors or pp60(c-src) siRNA significantly decreased the proliferation rate of NPM-ALK-positive ALCL cell lines. Moreover, using active or inactive forms of pp60(c-src) and NPM-ALK, we provide evidence that NPM-ALK is a potential substrate of pp60(c-src). Overall, our data place Src-kinases as new important downstream effectors of NPM-ALK and as attractive potential therapeutic targets for new ALCL treatment.
Cussac
Daniel
D
INSERM U563, CPTP, Departement d'Oncologenèse et Signalisation dans les Cellules Hématopoïétiques, Hôpital Purpan, 31059 Toulouse, France.
Greenland
Catherine
C
Roche
Serge
S
Bai
Ren-Yuan
RY
Duyster
Justus
J
Morris
Stephan W
SW
Delsol
Georges
G
Allouche
Michèle
M
Payrastre
Bernard
B
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division; D002889:Chromosomes, Human, Pair 2; D002895:Chromosomes, Human, Pair 5; D006801:Humans; D019169:Jurkat Cells; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D056489:Nucleoplasmins; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases; D014178:Translocation, Genetic; D014443:Tyrosine / Q000378:metabolism
D001798:Blood Proteins; D009687:Nuclear Proteins; D056489:Nucleoplasmins; D010750:Phosphoproteins; D014443:Tyrosine; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src)