Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas.
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.
Colomba
A
A
INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
Courilleau
D
D
Ramel
D
D
Billadeau
D D
DD
Espinos
E
E
Delsol
G
G
Payrastre
B
B
Gaits-Iacovoni
F
F
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000201:enzymology*; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000502:physiology; D000090243:Nucleophosmin; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism* / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism* / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases; D015398:Signal Transduction / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D019061:src-Family Kinases / Q000502:physiology
D000077548:Anaplastic Lymphoma Kinase; D000081247:CSK Tyrosine-Protein Kinase; D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D051567:Proto-Oncogene Proteins c-vav; D020794:Receptor Protein-Tyrosine Kinases; D020830:rac1 GTP-Binding Protein; D019061:src-Family Kinases; C000716967:NPM1 protein, human; C496621:VAV3 protein, human; C496622:Vav3 protein, mouse; C107023:p80(NPM-ALK) protein; C000626173:ALK protein, human; C000626174:Alk protein, mouse; C000631346:CSK protein, human