Expression of TSLP in pancreatic cancer correlates with Th2 deviation of antitumor immunity that is associated with decrease of patient survival.

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with Rett syndrome, West syndrome, and X-linked infantile spasms sharing the common features of generally intractable early seizures and mental retardation. Disease-causing mutations are distributed in both the catalytic domain and in the large COOH terminus. In this report, we examine the functional consequences of some Rett mutations of CDKL5 together with some synthetically designed derivatives useful to underline the functional domains of the protein. The mutated CDKL5 derivatives have been subjected to in vitro kinase assays and analyzed for phosphorylation of the TEY (Thr-Glu-Tyr) motif within the activation loop, their subcellular localization, and the capacity of CDKL5 to interact with itself. Whereas wild-type CDKL5 autophosphorylates and mediates the phosphorylation of the methyl-CpG-binding protein 2 (MeCP2) in vitro, Rett-mutated proteins show both impaired and increased catalytic activity suggesting that a tight regulation of CDKL5 is required for correct brain functions. Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif. Eventually, we show that the COOH terminus regulates CDKL5 properties; in particular, it negatively influences the catalytic activity and is required for its proper sub-nuclear localization. We propose a model in which CDKL5 phosphorylation is required for its entrance into the nucleus whereas a portion of the COOH-terminal domain is responsible for a stable residency in this cellular compartment probably through protein-protein interactions.X-linked cyclin-dependent kinase-like 5 (CDKL5, 3 previously named STK9) was originally identified in a transcriptional mapping project focused on the human chromosome Xp22.3-p21.3, spanning a region critical for several diseases. Expression studies demonstrated that CDKL5 was transcribed in several tissues, including brain (1). However, the possible link between CDKL5 and human diseases was drawn only few years later when balanced translocating events disrupting the gene were identified in two female patients affected by severe infantile spasms and mental retardation (2). Retrospectively, a previous publication had identified a large deletion involving CDKL5 in a male patient with X-linked retinoschisis and seizure (3); it has recently been hypothesized that retinoschisis is due to deletion of the XLRS1 gene, whereas epilepsy is caused by truncation of at least the last exon of CDKL5 (2). The importance of CDKL5 in early onset seizures and severe mental retardation in females has been further reinforced by five recent reports linking mutations in CDKL5 to patients with Rett syndrome but only in those affected by a variant form characterized by seizure onset before 6 months of age (4 -8). Very recently the frequency of CDKL5 mutations in patients affected by infantile spasms or early onset epilepsy of unknown cause has been investigated. The identification of several novel lik...

hMena (ENAH), an actin regulatory protein involved in the control of cell motility and adhesion, is modulated during human breast carcinogenesis. In fact, whereas undetectable in normal mammary epithelium, hMena becomes overexpressed in high-risk benign lesions and primary and metastatic tumors. In vivo, hMena overexpression correlates with the HER-2 +