Involvement of Grb2 Adaptor Protein in Nucleophosmin-Anaplastic Lymphoma Kinase (NPM-ALK)-mediated Signaling and Anaplastic Large Cell Lymphoma Growth |
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Authors: | Ludovica Riera Elena Lasorsa Chiara Ambrogio Nadia Surrenti Claudia Voena Roberto Chiarle |
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Institution: | From the ‡Center for Experimental Research and Medical Studies and ;the §Department of Biomedical Sciences and Human Oncology, University of Torino, 10126 Torino, Italy |
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Abstract: | Most anaplastic large cell lymphomas (ALCL) express oncogenic fusion proteins derived from chromosomal translocations or inversions of the anaplastic lymphoma kinase (ALK) gene. Frequently ALCL carry the t(2;5) translocation, which fuses the ALK gene to the nucleophosmin (NPM1) gene. The transforming activity mediated by NPM-ALK fusion induces different pathways that control proliferation and survival of lymphoma cells. Grb2 is an adaptor protein thought to play an important role in ALK-mediated transformation, but its interaction with NPM-ALK, as well as its function in regulating ALCL signaling pathways and cell growth, has never been elucidated. Here we show that active NPM-ALK, but not a kinase-dead mutant, bound and induced Grb2 phosphorylation in tyrosine 160. An intact SH3 domain at the C terminus of Grb2 was required for Tyr160 phosphorylation. Furthermore, Grb2 did not bind to a single region but rather to different regions of NPM-ALK, mainly Tyr152–156, Tyr567, and a proline-rich region, Pro415–417. Finally, shRNA knockdown experiments showed that Grb2 regulates primarily the NPM-ALK-mediated phosphorylation of SHP2 and plays a key role in ALCL cell growth. |
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Keywords: | Adaptor Proteins Leukemia Oncogene Receptor Tyrosine Kinase shRNA Signal Transduction Anaplastic Large Cell Lymphoma Grb2 NPM-ALK |
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