Showing papers by "Tak W. Mak published in 2007"
TL;DR: It is shown that Src homology 2 domain-containing inositol-5-phosphatase 1 (SHIP1), a PtdIns(3,4,5)P3 phosphatase, is a key regulator of neutrophil migration and governs the formation of the leading edge and polarization required for chemotaxis.
Abstract: Proper neutrophil migration into inflammatory sites ensures host defense without tissue damage. Phosphoinositide 3-kinase (PI(3)K) and its lipid product phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) regulate cell migration, but the role of PtdIns(3,4,5)P3-degrading enzymes in this process is poorly understood. Here, we show that Src homology 2 (SH2) domain-containing inositol-5-phosphatase 1 (SHIP1), a PtdIns(3,4,5)P3 phosphatase, is a key regulator of neutrophil migration. Genetic inactivation of SHIP1 led to severe defects in neutrophil polarization and motility. In contrast, loss of the PtdIns(3,4,5)P3 phosphatase PTEN had no impact on neutrophil chemotaxis. To study PtdIns(3,4,5)P3 metabolism in living primary cells, we generated a novel transgenic mouse (AktPH–GFP Tg) expressing a bioprobe for PtdIns(3,4,5)P3. Time-lapse footage showed rapid, localized binding of AktPH–GFP to the leading edge membrane of chemotaxing ship1+/+AktPH–GFP Tg neutrophils, but only diffuse localization in ship1−/−AktPH–GFP Tg neutrophils. By directing where PtdIns(3,4,5)P3 accumulates, SHIP1 governs the formation of the leading edge and polarization required for chemotaxis.
282 citations
TL;DR: A previously undescribed signaling pathway mediating Ang II-dependent activation of NF-κB, which is composed of three principal proteins, CARMA3, Bcl10, and MALT1, is characterized, which elucidate a concrete series of molecular events that link ligand activation of the type 1 Ang II receptor to stimulation of the NF-σκB transcription factor.
Abstract: Angiotensin II (Ang II) is a peptide hormone that, like many cytokines, acts as a proinflammatory agent and growth factor. After injury to the liver, the hormone assists in tissue repair by stimulating hepatocytes and hepatic stellate cells to synthesize extracellular matrix proteins and secrete secondary cytokines and by stimulating myofibroblasts to proliferate. However, under conditions of chronic liver injury, all of these effects conspire to promote pathologic liver fibrosis. Much of this effect of Ang II results from activation of the proinflammatory NF-κB transcription factor in response to stimulation of the type 1 Ang II receptor, a G protein-coupled receptor. Here, we characterize a previously undescribed signaling pathway mediating Ang II-dependent activation of NF-κB, which is composed of three principal proteins, CARMA3, Bcl10, and MALT1. Blocking the function of any of these proteins, through the use of either dominant-negative mutants, RNAi, or gene targeting, effectively abolishes Ang II-dependent NF-κB activation in hepatocytes. In addition, Bcl10−/− mice show defective hepatic cytokine production after Ang II treatment. Evidence also is presented that this pathway activates NF-κB through ubiquitination of IKKγ, the regulatory subunit of the IκB kinase complex. These results elucidate a concrete series of molecular events that link ligand activation of the type 1 Ang II receptor to stimulation of the NF-κB transcription factor. These findings also uncover a function of the CARMA, Bcl10, and MALT1 proteins in cells outside the immune system.
179 citations
TL;DR: Foxo3a not only is an effector of PKB but also integrates distinct signals to regulate gene expression in erythropoiesis, which helps to understand the interplay of SCF and Epo in maintaining the balance between renewal and differentiation during erythroid development.
Abstract: The cooperation of stem cell factor (SCF) and erythropoietin (Epo) is required to induce renewal divisions in erythroid progenitors, whereas differentiation to mature erythrocytes requires the presence of Epo only. Epo and SCF activate common signaling pathways such as the activation of protein kinase B (PKB) and the subsequent phosphorylation and inactivation of Foxo3a. In contrast, only Epo activates Stat5. Both Foxo3a and Stat5 promote erythroid differentiation. To understand the interplay of SCF and Epo in maintaining the balance between renewal and differentiation during erythroid development, we investigated differential Foxo3a target regulation by Epo and SCF. Expression profiling revealed that a subset of Foxo3a targets was not inhibited but was activated by Epo. One of these genes was Cited2. Transcriptional control of Epo/Foxo3a-induced Cited2 was studied and compared with that of the Epo-repressed Foxo3a target Btg1. We show that in response to Epo, the allegedly growth-inhibitory factor Foxo3a associates with the allegedly growth-stimulatory factor Stat5 in the nucleus, which is required for Epo-induced Cited2 expression. In contrast, Btg1 expression is controlled by the cooperation of Foxo3a with cyclic AMP- and Jun kinase-dependent Creb family members. Thus, Foxo3a not only is an effector of PKB but also integrates distinct signals to regulate gene expression in erythropoiesis.
82 citations
TL;DR: The 2007 Nobel Prize in Physiology or Medicine has been awarded to Mario Capecchi, Martin Evans, and Oliver Smithies for developing specific gene modification techniques and mouse embryonic stem cell technology that, when combined, enable the creation of "knockout" mice.
61 citations
TL;DR: Valpha14iNKT cell-mediated protection against the metastasis of melanoma cells to the lung was impaired in the absence of Pten, and the Pten/PI3K pathway is indispensable for the homeostasis and antitumor surveillance function of Valpha14 iNKT cells.
42 citations
TL;DR: In this paper, the Cre-loxP system was used to generate an endothelial cell-specific mutation of PTEN in mice, which enhances postnatal neovascularization, including tumour angiogenesis.
Abstract: PTEN (phosphatase and tensin homologue deleted on chromosome 10) is an important tumour-suppressor gene that encodes a 3-phosphatase. The major substrate of PTEN is PIP 3 (phosphatidylinositol 3,4,5-trisphosphate) generated by the action of PI3Ks (phosphoinositide 3-kinases). Hereditary mutation of PTEN causes tumour-susceptibility diseases such as Cowden disease. We used the Cre - loxP system to generate an endothelial cell-specific mutation of PTEN in mice. Heterozygous mutation of PTEN in endothelial cells enhances postnatal neovascularization, including tumour angiogenesis necessary for tumour growth. This observation suggests that Cowden disease patients are not only at risk for additional tumorigenic mutations due to complete loss of PTEN function, but may also experience accelerated growth of incipient tumours due to enhanced angiogenesis. Homozygous mutation of Pten in murine endothelial cells impairs cardiovascular morphogenesis and is embryonic lethal due to endothelial cell hyperproliferation and impaired vascular remodelling. Additional homozygous mutation of p85 α, the regulatory subunit of class IA PI3Ks, or p110 γ, the catalytic subunit of the sole class IB PI3K, led to a partial rescue of all phenotypes in our PTEN-deficient mice. Thus inhibition of the PI3K pathway, including the targeting of PI3Kγ, may be an attractive therapeutic strategy for the treatment of various malignancies.
22 citations
TL;DR: How the knowledge generated from the discovery of the TCR genes has been applied to basic and clinical immunology, and where it might take us in the future is discussed.
Abstract: The quest to clone the genes encoding the T cell antigen receptor (TCR) was a tale akin to Lewis Carroll's "The Hunting of the Snark". After a long and often frustrating search, back-to-back papers reporting the discovery of the genes encoding the mouse and human TCR were finally published in the March 8, 1984 edition of Nature. In this account, I outline how my laboratory hunted the human form of the Snark, and what our discovery meant to both the immunology community and me personally. Since the isolation of the TCR genes 23 years ago, more than 30,000 papers have been published on subjects as varied as central tolerance, peripheral tolerance, TCR crystal structure, and how TCR bind to peptide/MHC structures. Numerous clinical studies involving aspects of TCR biology have also been reported. Here, I briefly discuss how the knowledge generated from our discovery has been applied to basic and clinical immunology, and where it might take us in the future.
17 citations