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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2728-2736 |
| Number of pages | 9 |
| Journal | Oncogene |
| Volume | 27 |
| Issue number | 19 |
| DOIs | |
| State | Published - Apr 24 2008 |
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Keywords
- Anaplastic large cell lymphomas
- NPM-ALK
- Rho GTPases
- Vav3
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
- Genetics
Cite this
Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas. / Colomba, A.; Courilleau, D.; Ramel, D.; Billadeau, Daniel D; Espinos, E.; Delsol, G.; Payrastre, B.; Gaits-Iacovoni, F.
In: Oncogene, Vol. 27, No. 19, 24.04.2008, p. 2728-2736.Research output: Contribution to journal › Article
}
TY - JOUR
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, Daniel D
AU - Espinos, E.
AU - Delsol, G.
AU - Payrastre, B.
AU - Gaits-Iacovoni, F.
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
UR - http://www.scopus.com/inward/record.url?scp=42549168106&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=42549168106&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1210921
DO - 10.1038/sj.onc.1210921
M3 - Article
VL - 27
SP - 2728
EP - 2736
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 19
ER -