Functional identification of kinases essential for T-cell activation through a genetic suppression screen

Mack, Karl D.; Goetz, Melissa von; Lin, Monica; Venegas, Marina; Barnhart, Jerry R.; Lu, Yunzhe; Lamar, Betty; Stull, Robert; Silvin, Christopher; Owings, Pamela; Bih, Fong-Yih; Abo, Arie

doi:10.1016/j.imlet.2004.08.004

Cited by 18 publications

(7 citation statements)

References 96 publications

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“…The first shRNA, designated 1M4K4i, was based on the RNAi sequence described by Mack et al [36] and had the following sequence: 5′-GATCCGTGGTTGGAAATGGCACCTttcaagagaAGGTGCCATTTCCAACCACTTTTTGGAAAA-3′. The second shRNA, designated 2M4K4i, was based on the RNAi sequence described by Collins et al [37] and had the following sequence: 5′-GATCCGGGAAGGTCTATCCTCTTAttcaagagaTAAGAGGATAGACCTTCCCTTTTTGGAAAA-3′.…”

Section: Methodsmentioning

confidence: 99%

A Novel Interaction between Pyk2 and MAP4K4 Is Integrated with Glioma Cell Migration

Loftus

Yang

Kloss

et al. 2013

Journal of Signal Transduction

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Glioma cell migration correlates with Pyk2 activity, but the intrinsic mechanism that regulates the activity of Pyk2 is not fully understood. Previous studies have supported a role for the N-terminal FERM domain in the regulation of Pyk2 activity as mutations in the FERM domain inhibit Pyk2 phosphorylation. To search for novel protein-protein interactions mediated by the Pyk2 FERM domain, we utilized a yeast two-hybrid genetic selection to identify the mammalian Ste20 homolog MAP4K4 as a binding partner for the Pyk2 FERM domain. MAP4K4 coimmunoprecipitated with Pyk2 and was a substrate for Pyk2 but did not coimmunoprecipitate with the closely related focal adhesion kinase FAK. Knockdown of MAP4K4 expression inhibited glioma cell migration and effectively blocked Pyk2 stimulation of glioma cell. Increased expression of MAP4K4 stimulated glioma cell migration; however, this stimulation was blocked by knockdown of Pyk2 expression. These data support that the interaction of MAP4K4 and Pyk2 is integrated with glioma cell migration and suggest that inhibition of this interaction may represent a potential therapeutic strategy to limit glioblastoma tumor dispersion.

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Section: Methodsmentioning

confidence: 99%

A Novel Interaction between Pyk2 and MAP4K4 Is Integrated with Glioma Cell Migration

Loftus

Yang

Kloss

et al. 2013

Journal of Signal Transduction

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“…Thus, suppressors of JNK signaling may enhance insulin action and prevent defects in glucose metabolism after TNF-␣ stimulation. JNK is activated via a newly discovered protein named mitogenic-activated protein kinase kinase kinase kinase isoform 4 (MAP4K4) after treatment of cells with TNF-␣ (12)(13)(14)(15) or other chemokine-cytokines such as osteopontin (16). MAP4K4 is a member of the germinal center kinase group related to Saccharomyces cerevisiae MAP4K, Sterile 20 (17,18).…”

Section: From the Department Of Molecular Medicine And Surgery Karolmentioning

confidence: 99%

MAP4K4 Gene Silencing in Human Skeletal Muscle Prevents Tumor Necrosis Factor-α-induced Insulin Resistance

Bouzakri

Zierath

2007

Journal of Biological Chemistry

133

108

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Tumor necrosis factor-␣ (TNF-␣) induces skeletal muscle insulin resistance by impairing insulin signaling events involved in GLUT4 translocation. We tested whether mitogenic-activated protein kinase kinase kinase kinase isoform 4 (MAP4K4) causes the TNF-␣-induced negative regulation of extracellular signal-regulated kinase-1/2 (ERK-1/2), c-Jun NH 2 -terminal kinase (JNK), and the insulin receptor substrate-1 (IRS-1) on the insulin signaling pathway governing glucose metabolism. Using small interfering RNA (siRNA) to suppress the expression of MAP4K4 protein 85% in primary human skeletal muscle cells, we provide evidence that TNF-␣-induced insulin resistance on glucose uptake was completely prevented. MAP4K4 silencing inhibited TNF-␣-induced negative signaling inputs by preventing excessive JNK and ERK-1/2 phosphorylation, as well as IRS-1 serine phosphorylation. These results highlight the MAPK4K4/JNK/ERK/IRS module in the negative regulation of insulin signaling to glucose transport in response to TNF-␣. Depletion of MAP4K4 also prevented TNF-␣-induced insulin resistance on Akt and the Akt substrate 160 (AS160), providing evidence that appropriate insulin signaling inputs for glucose metabolism were rescued. Silencing of MAP2K1 and MAP2K4, signaling proteins downstream of MAP4K4, recapitulated the effect of MAP4K4 siRNA in TNF-␣-treated cells. Thus, strategies to inhibit MAP4K4 may be efficacious in the prevention of TNF-␣-induced inhibitory signals that cause skeletal muscle insulin resistance on glucose metabolism in humans. Moreover, in myotubes from insulin-resistant type II diabetic patients, siRNA against MAP4K4, MAP2K4, or MAP2K1 restored insulin action on glucose uptake to levels observed in healthy subjects. Collectively, our results demonstrate that MAP4K4 silencing prevents insulin resistance in human skeletal muscle and restores appropriate signaling inputs to enhance glucose uptake.

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“…It will be interesting to examine how the expression patterns (depending on lymphocyte type or burn-elicited stress) of these proviruses are correlated with the expression of the relevant genes, for example, the relationship between BM-a-2.11e MuLV-ERV, which was identified using a U3 probe uniquely identified from the B-cells of burn mice, and Camk2b (calcium/calmodulin-dependent protein kinase II-beta) locus. The Camk2b expression is associated with T-cell activation and cytotoxic T-cell activity [35,36]. It is possible that the burn-elicited stressors may affect the promoter and/or enhancer activities of certain MuLV-ERVs paralleling modulation of the expression of adjacent genes in a specific lymphocyte type.…”

Section: Resultsmentioning

confidence: 99%

Injury-elicited stressors alter endogenous retrovirus expression in lymphocytes depending on cell type and source lymphoid organ

et al. 2013

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BackgroundMurine leukemia virus-type endogenous retroviruses (MuLV-ERVs) constitute ~10% of the mouse genome and are associated with various pathophysiologic processes. In this study, we examined whether MuLV-ERVs’ response to burn-elicited stressors is specific for certain lymphocyte populations and/or locations of lymphoid organ.ResultsB- and T-cells, which were sorted from nine lymphoid organs of C57BL/6J mice after burn, were subjected to MuLV-ERV expression analyses. Overall, the post-burn MuLV-ERV expression pattern was dependent on lymphocyte type, time after injury, location of lymphoid organ, and MuLV-ERV type. For instance, the MuLV-ERV expression in T-cells from the thymus and three cervical lymph nodes decreased at 3 hours post-burn while the expression of some MuLV-ERVs was augmented in B-cells derived from the mesenteric lymph node. The MuLV-ERV U3 sequences population of the burn-24 hours group was less diverse in comparison to the no burn and burn-3 hours groups. In addition, it was apparent that at the 24 hours time point, the U3 populations of B-cells from both no burn and burn groups were less heterogeneous than the T-cells’ U3 populations. Using the U3 sequences, some of which were isolated only from specific experimental groups (B- vs. T-cells; no burn vs. burn), as probes, 51 putative MuLV-ERVs, including 16 full-length proviruses, were mapped followed by characterization of their biologic properties.ConclusionMuLV-ERVs’ response to burn-elicited stressors may be differentially controlled depending on lymphocyte type, location of lymphoid organ, MuLV-ERV type, and stress duration.

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Functional identification of kinases essential for T-cell activation through a genetic suppression screen

Cited by 18 publications

References 96 publications

A Novel Interaction between Pyk2 and MAP4K4 Is Integrated with Glioma Cell Migration

A Novel Interaction between Pyk2 and MAP4K4 Is Integrated with Glioma Cell Migration

MAP4K4 Gene Silencing in Human Skeletal Muscle Prevents Tumor Necrosis Factor-α-induced Insulin Resistance

Injury-elicited stressors alter endogenous retrovirus expression in lymphocytes depending on cell type and source lymphoid organ

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