Journal ArticleDOI
Pivotal role of phosphoinositide-3 kinase in regulation of cytotoxicity in natural killer cells.
Kun Jiang,Bin Zhong,Danielle L. Gilvary,Brian C. Corliss,Elizabeth Hong-Geller,Sheng Wei,Julie Y. Djeu +6 more
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TLDR
It is shown that inhibition of phosphoinositide-3 kinase (PI3K) in NK cells blocks p21-activated kinase 1 (PAK1), MAPK Kinase (MEK) and ERK activation by target cell ligation, interferes with perforin and granzyme B movement toward target cells and suppresses NK cytotoxicity.Abstract:
The mitogen-activated protein kinase-extracellular signal-regulated kinase signaling element (MAPK-ERK) plays a critical role in natural killer (NK) cell lysis of tumor cells, but its upstream effectors were previously unknown. We show that inhibition of phosphoinositide-3 kinase (PI3K) in NK cells blocks p21-activated kinase 1 (PAK1), MAPK kinase (MEK) and ERK activation by target cell ligation, interferes with perforin and granzyme B movement toward target cells and suppresses NK cytotoxicity. Dominant-negative N17Rac1 and PAK1 mimic the suppressive effects of PI3K inhibitors, whereas constitutively active V12Rac1 has the opposite effect. V12Rac1 restores the activity of downstream effectors and lytic function in LY294002- or wortmannin-treated, but not PD98059-treated, NK cells. These results document a specific PI3K-->Rac1-->PAK1-->MEK-->ERK pathway in NK cells that effects lysis.read more
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The phosphatidylinositol 3-Kinase AKT pathway in human cancer.
Igor Vivanco,Charles L. Sawyers +1 more
TL;DR: Small-molecule therapeutics that block PI3K signalling might deal a severe blow to cancer cells by blocking many aspects of the tumour-cell phenotype.
Journal ArticleDOI
Functional significance of the perforin/granzyme cell death pathway
Joseph A. Trapani,Mark J. Smyth +1 more
TL;DR: Critically recent findings on cytotoxic granule-mediated cell death are evaluated to assess the functional significance of postulated cell-death pathways in appropriate pathophysiological contexts, including virus infection and susceptibility to experimental or spontaneous tumorigenesis.
Journal ArticleDOI
Lymphocyte-Mediated Cytotoxicity
John H. Russell,Timothy J. Ley +1 more
TL;DR: The Fas/FasL system is responsible for activation-induced cell death but also plays an important role in lymphocyte-mediated killing under certain circumstances, and oversuppression of these pathways may also lead to increased viral susceptibility and/or decreased tumor cell killing.
Journal ArticleDOI
Coordinated Induction by IL15 of a TCR-Independent NKG2D Signaling Pathway Converts CTL into Lymphokine-Activated Killer Cells in Celiac Disease
Bertrand Meresse,Zhangguo Chen,Cezary Ciszewski,Maria Tretiakova,Govind Bhagat,Thomas Krausz,David H. Raulet,Lewis L. Lanier,Veronika Groh,Thomas Spies,Ellen C. Ebert,Peter H.R. Green,Bana Jabri +12 more
TL;DR: It is shown that, under conditions of dysregulated IL15 expression in vivo in patients with celiac disease and in vitro in healthy individuals, multiple steps of the NKG2D/DAP10 signaling pathway leading to ERK and JNK activation are coordinately primed to activate direct cytolytic function independent of TCR specificity in effector CD8 T cells.
Journal ArticleDOI
Natural killer cell signaling pathways.
TL;DR: The tyrosine-phosphorylation status of several signaling components that are substrates for both PTKs and PTPs is thus key to the propagation of the NK cell effector pathways.
References
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Journal ArticleDOI
The small GTP-binding proteins Rac1 and Cdc42regulate the activity of the JNK/SAPK signaling pathway
Omar A. Coso,Mario Chiariello,Jin-Chen Yu,Hidemi Teramoto,Piero Crespo,Ningzhi Xu,Toru Miki,J. Silvio Gutkind +7 more
TL;DR: It is shown that in COS-7 cells, activated Ras effectively stimulates MAPK but poorly induces JNK activity, which strongly support a critical role for Rac1 and Cdc42 in controlling the JNK signaling pathway.
Journal ArticleDOI
LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation.
TL;DR: The cloning of the cDNA is reported for a highly tyrosine-phosphorylated 36-38 kDa protein, previously characterized by its association with Grb2, phospholipase C-gamma1, and the p85 subunit of phosphoinositide 3-kinase, which is phosphorylated by ZAP-70/Syk protein tyrosines leading to recruitment of multiple signaling molecules.
Journal ArticleDOI
Function of PI3Kγ in Thymocyte Development, T Cell Activation, and Neutrophil Migration
Takehiko Sasaki,Junko Irie-Sasaki,Junko Irie-Sasaki,Russell G. Jones,Antonio J. Oliveira-dos-Santos,William L. Stanford,Brad Bolon,Andrew Wakeham,Annick Itie,Dennis Bouchard,Ivona Kozieradzki,Nicholas Joza,Tak W. Mak,Tak W. Mak,Pamela S. Ohashi,Akira Suzuki,Akira Suzuki,Josef M. Penninger,Josef M. Penninger +18 more
TL;DR: It is shown that PI3Kgamma controls thymocyte survival and activation of mature T cells but has no role in the development or function of B cells.
Journal ArticleDOI
Antiapoptotic signalling by the insulin-like growth factor i receptor, phosphatidylinositol 3-kinase, and akt
TL;DR: It is found that insulin-like growth factor I (IGF-I) can protect fibroblasts from apoptosis induced by UV-B light, and that activation of PI3 kinase and Akt is sufficient for antiapoptotic signalling.
Journal ArticleDOI
Role of Substrates and Products of PI 3-kinase in Regulating Activation of Rac-Related Guanosine Triphosphatases by Vav
Jaewon Han,Katherine Luby-Phelps,Balaka Das,Xiaodong Shu,Yi Xia,Raymond D. Mosteller,U. Murali Krishna,John R. Falck,Michael A. White,Daniel Broek +9 more
TL;DR: Control of Vav in response to mitogens by the products of PI 3-kinase suggests a mechanism for Ras-dependent activation of Rac.