A "liaison dangereuse" between AUF1/hnRNPD and the oncogenic tyrosine kinase NPM-ALK

Abstract

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...

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

“…With this goal in mind, several large or medium scale proteomic and transcriptomic studies were undertaken by several groups Lim and Elenitoba-Johnson, 2006). New partners have been found that account for different functions of NPM-ALK, such as the regulation of mRNA turnover (Fawal et al, 2006). Among others, proteins regulating cell shape and cytoskeleton plasticity, two important features altered in transformed cells, were identified, leading to investigations of molecules classified as 'cytoskeleton and motility regulators' in the context of ALCLs (Crockett et al, 2004;Cussac et al, 2006).…”

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

“…COST and NIH-3T3 cells were fixed, permeabilized, and stained as described in the work of Fawal and colleagues (18). Polyclonal anti-HuR and monoclonal anti-ALK1 antibodies were used.…”

Involvement of the RNA-binding protein ARE/poly(U)-binding factor 1 (AUF1) in the cytotoxic effects of proinflammatory cytokines on pancreatic beta cells

“…The localisation of AUF1 can be influenced by a variety of factors including: the presence or absence of exons containing nuclear localisation signals [33,34]; interaction with transporters [35] or chaperones [36,37]; protein ubiquitination [13]; and phosphorylation of specific residues [7,38]. At steady-state, most AUF1 isoforms accumulate in the nucleus but are partially relocalised upon exposure of insulin-secreting cells to proinflammatory cytokines.…”