IntroductionAnaplastic large cell lymphoma (ALCL) is a T/null-cell neoplasm characterized by the expression of a hybrid protein comprising an N-terminal partner protein fused to the cytoplasmic portion of the anaplastic lymphoma kinase (ALK) tyrosine kinase. The fulllength ALK protein belongs to the family of receptor tyrosine kinases and is highly conserved across species. 1 In approximately 80% of ALK-positive lymphomas, the hybrid kinase is the NPM-ALK fusion protein that is encoded by the nucleophosmin (NPM)-ALK fusion gene resulting from the (2;5)(p23;q35) chromosomal translocation. [2][3][4] Other translocations have been described involving the ALK gene and other partners, including TFG, 5 CLTC, 6 ATIC, 6,7 and TPM3. 8 In NPM-ALK, as well as in variant fusion proteins, the N-terminal partner protein is widely expressed in normal cells due to ubiquitous transcription of the corresponding promoter. Thus, cells that do not normally express the full-length ALK receptor because of its restricted tissue distribution 4,9 display, if they contain an X-ALK translocation, anomalous transcription of the ALK chimeric mRNA and aberrant expression of the encoded fusion protein. In addition, the N-terminal partner protein (NPM or other variants) contains an oligomerization motif that enables the fusion protein to form homodimers as well as heterodimers with the full-length partner (Bischof et al 10 and review in Pulford et al 1 ). Oligomerization of the fusion protein results in the constitutive activation of the ALK tyrosine kinase catalytic domain contained in its carboxy-terminal part. This, in turn, leads to abnormal activation of multiple downstream signaling cascades that are responsible for the neoplastic transformation of cells, involving, among others, phospholipase C-gamma (PLC␥), 11 phosphoinositide 3-kinase (PI3K), 12 13,15 as well as Src kinases. 16 Several model systems have been established to study the oncogenic mechanisms used by ALK fusion proteins, including transgenic mice, which develop lymphoma when NPM-ALK expression is directed to lymphocytes, 17,18 and cultured cells which acquire transformed properties when they express ALK fusion . A recent analysis of NPM-ALK-associated proteins in the t(2;5)-positive line Karpas 299 led to the identification of a number of proteins and highlighted the complexity of the molecular mechanisms underlying NPM-ALK oncogenicity. 20 In this study, we characterized AUF1/hnRNPD as a new partner of NPM-ALK. AUF1 belongs to the family of AU-binding proteins (AU-BPs) that regulate the cellular half-lives of many mRNAs by directly interacting with an AU-rich element (ARE) located in their 3Ј untranslated region. [21][22][23] Although AREs are found in mRNAs coding for a wide range of proteins, 24 many ARE-containing mRNAs are transcribed from early response genes (ERGs) encoding proto-oncogene products (such as c-Myc), cytokines, cyclins (such as cyclins D1, A2, and B1) and growth factors involved in the control of cell growth and proliferation. Here, we demonstrate that...

In relation to the activation of the Src-family of tyrosine kinases during early morphogenetic events of gastrulation in Xenopus, we have identified two multiprotein complexes. The first complex, including RasGAP, p190 RhoGAP and p62, was previously characterized in murine fibroblasts overexpressing c-Src or transformed by v-Src and has been correlated with cytoskeleton remodelling. A second complex, not identified in other models includes tyrosine-phosphorylated p66SHC, Grb2, RasGAP and p190 RhoGAP. The association with p66SHC, considered as a negative regulator of ERK (extracellular signal-regulated kinase), p120RasGAP and p190RhoGAP, suggests a possible mechanism for coupling Ras and Rho signalling pathways. The interaction of RasGAP and p190 RhoGAP in two multiprotein complexes could constitute an additional level of Rho regulation during morphogenetic events of gastrulation.Keywords: RasGAP; p190RhoGAP; cytoskeleton; gastrulation.During embryogenesis in vertebrates, cell rearrangements participate in many morphogenetic events. In Xenopus, the gastrulation is preceded by epithelial cell rearrangements of the animal cap, which are responsible for epiboly, a morphogenetic process in which the ectodermal cells expand to cover a large surface of the gastrula [1,2]. In this process, alterations in cell± cell adhesion are likely to play a role in controlling the morphogenetic rearrangement of cells. Likewise, a decrease in cell adhesion to the substrate seems to be associated with the enhanced motility of individual cells. In order to rearrange within epithelial sheets, cells need to be able to break and remake contact rapidly with their neighbours [3]. Thus dynamic adhesive interactions with the substrate are accompanied by a continuous reorganization of the actin cytoskeleton. One of the mechanisms implicated in the modulation of cell adhesion and cytoskeletal reorganization involves protein phosphorylation on tyrosine residues and Rho-GTPases [4±8]. Adhesion of cells to the extracellular matrix (ECM) activates, via integrins, a set of protein tyrosine kinases and triggers the formation of protein complexes on the cytoplasmic face of the plasma membrane [9±12]. Focal adhesions anchor the actin cytoskeleton to the plasma membrane and contain various proteins, including pp125 FAK and pp60 c-Src , which are implicated in the activation of signalling pathways [13±15].These multifunctional complexes, which can be considered as levels of integration of various signals generated by cell interactions, participate in signalling pathways, cytoskeleton reorganization and transcriptional regulation [16,17]. Focal adhesion complexes control the organization of the actin cytoskeleton via the regulation of Rho family GTPases, which belong to the ras superfamily of small GTPases [18±20]. It is becoming clear that actin reorganization is an integral part of early signal transduction pathways and that many signalling molecules interact with the actin cytoskeleton. Thus the translocation of Src from its site of synthesis to its si...

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