We have investigated the regulation of protein tyrosine phosphatases (PTPs) by reactive oxygen species (ROS) in a cellular environment. We demonstrate that multiple PTPs were reversibly oxidized and inactivated following treatment of Rat-1 cells with H(2)O(2) and that inhibition of PTP function was important for ROS-induced mitogenesis. Furthermore, we show transient oxidation of the SH2 domain containing PTP, SHP-2, in response to PDGF that requires association with the PDGFR. Our results indicate that SHP-2 inhibits PDGFR signaling and suggest a mechanism by which autophosphorylation of the PDGFR occurs despite its association with SHP-2. The data suggest that several PTPs may be regulated by oxidation and that characterization of this process may define novel links between specific PTPs and particular signaling pathways in vivo.

gp130 is a common signal transducer for the interleukin-6-related cytokines. To delineate the gp130-mediated growth signal, we established a series of pro-B cell lines expressing chimeric receptors composed of the extracellular domain of the granulocyte colony-stimulating factor receptor and the transmembrane and cytoplasmic domains of gp130. The second tyrosine (from the membrane) of gp130, which was required for the tyrosine phosphorylation of SHP-2, its association with GRB2, and activation of a MAP kinase, was essential for mitogenesis, but not for anti-apoptosis. On the other hand, the tyrosine in the YXXQ motifs essential for STAT3 activation was required for bcl-2 induction and anti-apoptosis. Furthermore, dominant-negative STAT3 inhibited anti-apoptosis. These data demonstrate that two distinct signals, mitogenesis and anti-apoptosis, are required for gp130-induced cell growth and that STAT3 is involved in anti-apoptosis.

Interleukin‐6 (IL‐6) induces either differentiation or growth of a variety of cells. Little is known about the molecular basis of this cellular decision. The family of signal transducer and activator of transcription (Stat) proteins are involved in signaling through a variety of cytokine and growth factor receptors, although their biological roles have not been established. To address whether Stat proteins play roles in IL‐6‐induced growth or differentiation, we introduced two types of mutant Stat3 acting in a dominant‐negative manner into M1 leukemic cells which respond to IL‐6 with growth arrest and terminal differentiation. We show that dominant‐negative forms of Stat3 inhibited both IL‐6‐induced growth arrest at G(0)/G1 and macrophage differentiation in the M1 transformants. Blocking of Stat activation resulted in inhibition of IL‐6‐induced repression of c‐myb and c‐myc. Furthermore, IL‐6 enhanced the growth of M1 cells primarily through shortening the length of the G1 period when Stat3 was suppressed. Thus IL‐6 generates both growth‐enhancing signals and growth arrest‐ and differentiation‐inducing signals at the same time. Stat3 may be a key molecule which determines the cellular decision from cell growth to differentiation in M1 cells.

The essential trace element zinc (Zn) is widely required in cellular functions, and abnormal Zn homeostasis causes a variety of health problems that include growth retardation, immunodeficiency, hypogonadism, and neuronal and sensory dysfunctions. Zn homeostasis is regulated through Zn transporters, permeable channels, and metallothioneins. Recent studies highlight Zn’s dynamic activity and its role as a signaling mediator. Zn acts as an intracellular signaling molecule, capable of communicating between cells, converting extracellular stimuli to intracellular signals, and controlling intracellular events. We have proposed that intracellular Zn signaling falls into two classes, early and late Zn signaling. This review addresses recent findings regarding Zn signaling and its role in physiological processes and pathogenesis.

The activation of STAT3 by the cytokine receptor gp130 is required for both the G1 to S cell cycle transition and antiapoptosis. We found that Pim-1 and Pim-2 are targets for the gp130-mediated STAT3 signal. Expression of a kinase-defective Pim-1 mutant attenuated gp130-mediated cell proliferation. Constitutive expression of Pim-1 together with c-myc, another STAT3 target, fully compensated for loss of the STAT3-mediated cell cycle progression, antiapoptosis, and bcl-2 expression. We also identified valosine-containing protein (VCP) as a target gene for the Pim-1-mediated signal. Expression of a mutant VCP led cells to undergo apoptosis. These results indicate that Pim-family proteins play crucial roles in gp130-mediated cell proliferation and explain the synergy between Pim and c-Myc proteins in cell proliferation and lymphomagenesis.

Zinc is a trace element that is essential for the function of many enzymes and transcription factors. Zinc deficiency results in defects in innate and acquired immune responses. However, little is known about the mechanism(s) by which zinc affects immune cell function. Here we show that stimulation with the Toll-like receptor 4 agonist lipopolysaccharide (LPS) altered the expression of zinc transporters in dendritic cells and thereby decreased intracellular free zinc. A zinc chelator mimicked the effects of LPS, whereas zinc supplementation or overexpression of the gene encoding Zip6, a zinc transporter whose expression was reduced by LPS, inhibited LPS-induced upregulation of major histocompatibility complex class II and costimulatory molecules. These results establish a link between Toll-like receptor signaling and zinc homeostasis.

Vertebrate gastrulation is a critical step in the establishment of body plan. During gastrulation, epithelial-mesenchymal transition (EMT) occurs. EMT is one of the central events of embryonic development, organ and tissue regeneration, and cancer metastasis. Signal transducers and activators of transcription (STATs) mediate biological actions such as cell proliferation, differentiation and survival in response to cytokines and growth factors, in a variety of biological processes. STATs are also important in EMT during gastrulation, organogenesis, wound healing and cancer progression. We previously showed that STAT3 is activated in the organizer during zebrafish gastrulation and its activity is essential for gastrulation movements. The requirement for STAT3 is cell-autonomous for the anterior migration of gastrula organizer cells, and non-cell-autonomous for the convergence of neighbouring cells. The molecular mechanisms of STAT's action in EMT, however, are unknown. Here we identify LIV1, a breast-cancer-associated zinc transporter protein, as a downstream target of STAT3 that is essential and sufficient for STAT3's cell-autonomous role in the EMT of zebrafish gastrula organizer cells. Furthermore, we demonstrate that LIV1 is essential for the nuclear localization of zinc-finger protein Snail, a master regulator of EMT. These results establish a molecular link between STAT3, LIV1 and Snail in EMT.

Background: Zinc (Zn) is an essential trace element and it is abundant in connective tissues, however biological roles of Zn and its transporters in those tissues and cells remain unknown.