Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas

A. Colomba; D. Courilleau; D. Ramel; D. D. Billadeau; E. Espinos; G. Delsol; B. Payrastre; F. Gaits-Iacovoni

doi:10.1038/sj.onc.1210921

Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas

A. Colomba, D. Courilleau, D. Ramel, D. D. Billadeau, E. Espinos, G. Delsol, B. Payrastre, F. Gaits-Iacovoni

Oncology

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

Abstract

The majority of anaplastic large cell lymphomas (ALCLs) express the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion protein, which is oncogenic due to its constitutive tyrosine kinase activity. Transformation by NPM-ALK not only increases proliferation, but also modifies cell shape and motility in both lymphoid and fibroblastic cells. We report that the Rac1 GTPase, a known cytoskeletal regulator, is activated by NPM-ALK in ALCL cell lines (Karpas 299 and Cost) and transfected cells (lymphoid Ba/F3 cells, NIH-3T3 fibroblasts). We have identified Vav3 as one of the exchange factors involved in Rac1 activation. Stimulation of Vav3 and Rac1 by NPM-ALK is under the control of Src kinases. It involves formation of a signaling complex between NPM-ALK, pp60^c-src, Lyn and Vav3, in which Vav3 associates with tyrosine 343 of NPM-ALK via its SH2 domain. Moreover, Vav3 is phosphorylated in NPM-ALK positive biopsies from patients suffering from ALCL, demonstrating the pathological relevance of this observation. The use of Vav3-specific shRNA and a dominant negative Rac1 mutant demonstrates the central role of GTPases in NPM-ALK elicited motility and invasion.

Original language	English (US)
Pages (from-to)	2728-2736
Number of pages	9
Journal	Oncogene
Volume	27
Issue number	19
DOIs	https://doi.org/10.1038/sj.onc.1210921
State	Published - Apr 24 2008

Keywords

Anaplastic large cell lymphomas
NPM-ALK
Rho GTPases
Vav3

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

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title = "Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas",

abstract = "The majority of anaplastic large cell lymphomas (ALCLs) express the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion protein, which is oncogenic due to its constitutive tyrosine kinase activity. Transformation by NPM-ALK not only increases proliferation, but also modifies cell shape and motility in both lymphoid and fibroblastic cells. We report that the Rac1 GTPase, a known cytoskeletal regulator, is activated by NPM-ALK in ALCL cell lines (Karpas 299 and Cost) and transfected cells (lymphoid Ba/F3 cells, NIH-3T3 fibroblasts). We have identified Vav3 as one of the exchange factors involved in Rac1 activation. Stimulation of Vav3 and Rac1 by NPM-ALK is under the control of Src kinases. It involves formation of a signaling complex between NPM-ALK, pp60c-src, Lyn and Vav3, in which Vav3 associates with tyrosine 343 of NPM-ALK via its SH2 domain. Moreover, Vav3 is phosphorylated in NPM-ALK positive biopsies from patients suffering from ALCL, demonstrating the pathological relevance of this observation. The use of Vav3-specific shRNA and a dominant negative Rac1 mutant demonstrates the central role of GTPases in NPM-ALK elicited motility and invasion.",

keywords = "Anaplastic large cell lymphomas, NPM-ALK, Rho GTPases, Vav3",

author = "A. Colomba and D. Courilleau and D. Ramel and Billadeau, {D. D.} and E. Espinos and G. Delsol and B. Payrastre and F. Gaits-Iacovoni",

note = "Funding Information: We thank Dr Popoff for Clostridium lethal toxins. We are grateful to Dr H Tronch{\`e}re, Dr S Manenti, Dr MP Gratacap, Dr C Racaud-Sultan and Dr M Plantavid for helpful discussions. AC and DR were financed by the {\textquoteleft}Minist{\`e}re de la Recherche et de la Technologie{\textquoteright} and the {\textquoteleft}Association pour la Recherche sur le Cancer{\textquoteright}. This work was supported by grants from the INSERM, ARC, ARECA, La Ligue contre le Cancer, the {\textquoteleft}Canc{\'e}rop{\^o}le Grand Sud-Ouest{\textquoteright} and the {\textquoteleft}Institut National du Cancer{\textquoteright} (INCa), the R{\'e}gion Midi-Pyr{\'e}n{\'e}es and the {\textquoteleft}P{\^o}le de Comp{\'e}titivit{\'e} Cancer-Bio Sant{\'e}{\textquoteright}.",

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doi = "10.1038/sj.onc.1210921",

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T1 - Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas

AU - Colomba, A.

AU - Courilleau, D.

AU - Ramel, D.

AU - Billadeau, D. D.

AU - Espinos, E.

AU - Delsol, G.

AU - Payrastre, B.

AU - Gaits-Iacovoni, F.

N1 - Funding Information: We thank Dr Popoff for Clostridium lethal toxins. We are grateful to Dr H Tronchère, Dr S Manenti, Dr MP Gratacap, Dr C Racaud-Sultan and Dr M Plantavid for helpful discussions. AC and DR were financed by the ‘Ministère de la Recherche et de la Technologie’ and the ‘Association pour la Recherche sur le Cancer’. This work was supported by grants from the INSERM, ARC, ARECA, La Ligue contre le Cancer, the ‘Cancéropôle Grand Sud-Ouest’ and the ‘Institut National du Cancer’ (INCa), the Région Midi-Pyrénées and the ‘Pôle de Compétitivité Cancer-Bio Santé’.

PY - 2008/4/24

Y1 - 2008/4/24

N2 - The majority of anaplastic large cell lymphomas (ALCLs) express the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion protein, which is oncogenic due to its constitutive tyrosine kinase activity. Transformation by NPM-ALK not only increases proliferation, but also modifies cell shape and motility in both lymphoid and fibroblastic cells. We report that the Rac1 GTPase, a known cytoskeletal regulator, is activated by NPM-ALK in ALCL cell lines (Karpas 299 and Cost) and transfected cells (lymphoid Ba/F3 cells, NIH-3T3 fibroblasts). We have identified Vav3 as one of the exchange factors involved in Rac1 activation. Stimulation of Vav3 and Rac1 by NPM-ALK is under the control of Src kinases. It involves formation of a signaling complex between NPM-ALK, pp60c-src, Lyn and Vav3, in which Vav3 associates with tyrosine 343 of NPM-ALK via its SH2 domain. Moreover, Vav3 is phosphorylated in NPM-ALK positive biopsies from patients suffering from ALCL, demonstrating the pathological relevance of this observation. The use of Vav3-specific shRNA and a dominant negative Rac1 mutant demonstrates the central role of GTPases in NPM-ALK elicited motility and invasion.

AB - The majority of anaplastic large cell lymphomas (ALCLs) express the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion protein, which is oncogenic due to its constitutive tyrosine kinase activity. Transformation by NPM-ALK not only increases proliferation, but also modifies cell shape and motility in both lymphoid and fibroblastic cells. We report that the Rac1 GTPase, a known cytoskeletal regulator, is activated by NPM-ALK in ALCL cell lines (Karpas 299 and Cost) and transfected cells (lymphoid Ba/F3 cells, NIH-3T3 fibroblasts). We have identified Vav3 as one of the exchange factors involved in Rac1 activation. Stimulation of Vav3 and Rac1 by NPM-ALK is under the control of Src kinases. It involves formation of a signaling complex between NPM-ALK, pp60c-src, Lyn and Vav3, in which Vav3 associates with tyrosine 343 of NPM-ALK via its SH2 domain. Moreover, Vav3 is phosphorylated in NPM-ALK positive biopsies from patients suffering from ALCL, demonstrating the pathological relevance of this observation. The use of Vav3-specific shRNA and a dominant negative Rac1 mutant demonstrates the central role of GTPases in NPM-ALK elicited motility and invasion.

KW - Anaplastic large cell lymphomas

KW - NPM-ALK

KW - Rho GTPases

KW - Vav3

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AN - SCOPUS:42549168106

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JO - Oncogene

JF - Oncogene

SN - 0950-9232

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ER -

Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas

Abstract

Keywords

ASJC Scopus subject areas

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