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, 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.

HuR-Mediated Control of C/EBPβ mRNA Stability and Translation in ALK-Positive Anaplastic Large Cell Lymphomas

“…As a first step toward testing this model, we employed various in vitro and in vivo approaches and showed that HuR is indeed phosphorylated on tyrosine residue in ALK þ cells and that this phosphorylation required an active NPM-ALK protein. Whether tyrosine phosphorylation is directly executed by NPM-ALK or carried out by its associated tyrosine kinases, such as pp60c-src and Lyn (32,33), remains to be elucidated. Also, since HuR contains 10 tyrosine residues that are all potential targets for tyrosine kinases, in-depth studies will be necessary to precisely map the phosphorylated tyrosine residue(s), and evaluate their potential impact on serine and/or threonine residue phosphorylation.…”

Novel Interaction between the Co-chaperone Cdc37 and Rho GTPase Exchange Factor Vav3 Promotes Androgen Receptor Activity and Prostate Cancer Growth*

“…Vav3 overexpression is correlated with poor differentiation of breast cancer and is a predictor of decreased survival in patients with glioblastoma (12). Vav3 also plays a role in the development of anaplastic large cell lymphomas (13). Vav3 is up-regulated in human gastric cancer, and Vav3 overexpression is inversely correlated with gastric cancer patient survival (14).…”

“…Vav3 may also participate in other human cancers (12)(13)(14)(15). Vav3 overexpression is correlated with poor differentiation of breast cancer and is a predictor of decreased survival in patients with glioblastoma (12).…”

Reactive oxygen species and lipoxygenases regulate the oncogenicity of NPM-ALK-positive anaplastic large cell lymphomas

“…NPM-ALK mediates cellular transformation by taking control of signaling pathways involved in proliferation (for example, adaptors, mitogen-activated protein kinases (MAPKs), phospholipase Cg, protein tyrosine phosphatases (PTPs) or pp60 cÀsrc ), and in survival or antiapoptotic functions (phosphatidylinositol 3-kinase, PI3K/Akt pathway, or the Jak/ signal transducer and activator of transcription protein (STAT3-5) module) (Chiarle et al, 2008). NPM-ALK( þ ) neoplasias are very aggressive and cells display a very distorted morphology with increased invasion capabilities resulting from modifications of the cytoskeleton dynamics through proteins such as p130Crk-associated substrate (p130Cas) and Rac1 guanosine triphosphate phosphatase (GTPase) (Ambrogio et al, 2005;Colomba et al, 2008).…”