Wnt5a is a member of the Wnt family of secreted glycoproteins that play essential organizing roles in development. Similar to other Wnt members, Wnt5a can upregulate cell proliferation and has been proposed to have oncogenic function. Here we report that Wnt5a signals through the noncanonical Wnt/Ca++ pathway to suppress cyclin D1 expression and negatively regulate B cell proliferation in a cell-autonomous manner. Wnt5a hemizygous mice develop myeloid leukemias and B cell lymphomas that are clonal in origin and display loss of Wnt5a function in tumor tissues. Furthermore, analysis of human primary leukemias reveals deletion of the WNT5A gene and/or loss of WNT5A expression in a majority of the patient samples. These results demonstrate that Wnt5a suppresses hematopoietic malignancies.

SummaryDrosophila Pumilio (Pum) protein is a founder member of a novel family of RNA-binding proteins, known as the PUF family. The PUF proteins constitute an evolutionarily highly conserved family of proteins present from yeast to humans and plants, and are characterized by a highly conserved C-terminal RNA-binding domain, composed of eight tandem repeats. The conserved biochemical features and genetic function of PUF family members have emerged from studies of model organisms. PUF proteins bind to related sequence motifs in the 3' untranslated region (3'UTR) of specific target mRNAs and repress their translation. Frequently, PUF proteins function asymmetrically to create protein gradients, thus causing asymmetric cell division and regulating cell fate specification. Thus, it was recently proposed that the primordial role of PUF proteins is to sustain mitotic proliferation of stem cells. Here we review the evolution, conserved genetic and biochemical properties of PUF family of proteins, and discuss protein interactions, upstream regulators and downstream targets of PUF proteins. We also suggest that a conserved mechanism of PUF function extends to the newly described mammalian members of the PUF family (human PUM1 and PUM2, and mouse Pum1 and Pum2), that show extensive homology to Drosophila Pum, and could have an important role in cell development, fate specification and differentiation.

MAPKs are activated by a wide range of diverse stimuli and are essential for various cellular processes, such as stress responses, apoptosis, proliferation, differentiation, and early embryonic development (1-3). The prototypical MAPK signaling cascade is a three-kinase module, consisting of MAP kinase kinase kinase (MAP3K), MAP kinase kinase (MAP2K), and MAPK (1, 2, 4). The upstream molecules that link the MAPK module to extracellular stimuli include small G proteins and a group of mammalian Ste20-like kinases, including hematopoietic progenitor kinase 1 (HPK1), germinal center kinase (GCK), HKP1/germinal center kinase-like kinase, germinal center kinase-like kinase (GLK), and kinase homologous to Ste20 (KHS), which have been characterized as potential MAP kinase kinase kinase kinases (MAP4Ks) for the JNK pathway (1, 2, 4, 5). Within the three-kinase module, MAPKs are phosphorylated on both threonine and tyrosine residues within their signature sequence TXY motif by a dual specificity protein kinase MAP2K. These motifs include TEY in ERK, TPY in JNK, and TGY in p38. MAP2K are activated by phosphorylation of serine/threonine residues by MAP3Ks (1, 2, 4). In the case of ERK1/2, phosphorylation of the TEY motif also contributes to the dimerization and nuclear translocation of ERK1/2 in addition to mediating its activation (6). The extracellular stimuli-induced activation of MAPKs is transient under many conditions, and it has been well established that protein phosphatases play an essential role in the down-regulation of MAP kinases. A variety of classes of protein phosphatases, including tyrosine-specific protein phosphatases, serine/threonine protein phosphatases, and a family of dual specificity protein phosphatases (DSPs), have been implicated in the negative regulation of MAPKs (7-9). Among them, DSPs are the major group of phosphatases that contribute to the regulated inactivation of MAP kinases by dephosphorylating both phosphotyrosine and phosphothreonine residues within the TXY motif, thus also called MAP kinase phosphatases (MKPs) (7-9). Most MKPs identified so far consist of a conserved catalytic region and an extended regulatory region. However, some MKPs lack this regulatory region, such as VH1 (10) and VH1-related (VHR) phosphatase (11). The regulatory

We have generated mice with a null mutation at the Ada locus, which encodes the purine catabolic enzyme adenosine deaminase (ADA, EC 3.5.4.4

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