p38 Kinase-dependent MAPKAPK-2 Activation Functions as 3-Phosphoinositide-dependent Kinase-2 for Akt in Human Neutrophils

Rane, Madhavi J.; Coxon, Patricia Y.; Powell, Dave W.; Webster, Rose P.; Klein, Jon B.; Pierce, William M.; Ping, Peipei; McLeish, Kenneth R.

doi:10.1074/jbc.m005953200

Cited by 253 publications

(262 citation statements)

References 40 publications

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“…It has been shown to phosphorylate 27-kDa heat shock protein (21), the light chain of myosin II (12), and vimentin (5) and to be involved in cytoskeletal reorganization and migration (13). Furthermore, MAPKAPK-2 phosphorylates Akt on Ser 473 in vitro (1), and a peptide inhibitor of MAPKAPK-2 blocks Ser 473 phosphorylation in neutrophils stimulated with f-Met-Leu-Phe (18). Our data extend these in vitro observations to VSMCs and provide a mechanism by which the activation of MAPKAPK-2 and its interaction with Akt occur.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that p38 MAPK and Akt are able to associate with each other in human neutrophils (18). To determine whether such an association might facilitate Akt phosphorylation by p38 MAPK-dependent mechanisms in VSMCs, we performed immunoprecipitation followed by immunoblotting to investigate a possible interaction of these two kinases in VSMCs.…”

Section: Effect Of P38 Mapk Inhibition On Ang Ii-induced Akt Phosphormentioning

confidence: 99%

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Role of p38 MAPK and MAPKAPK-2 in angiotensin II-induced Akt activation in vascular smooth muscle cells

Taniyama¹,

Ushio‐Fukai²,

Hitomi³

et al. 2004

American Journal of Physiology-Cell Physiology

112

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II activates a variety of signaling pathways in vascular smooth muscle cells (VSMCs), including the MAPKs and Akt, both of which are required for hypertrophy. However, little is known about the relationship between these kinases or about the upstream activators of Akt. In this study, we tested the hypothesis that the reactive oxygen species (ROS)-sensitive kinase p38 MAPK and its substrate MAPKAPK-2 mediate Akt activation in VSMCs. In unstimulated VSMCs, Akt and p38 MAPK are constitutively associated and remain so after angiotensin II stimulation. Inhibition of p38 MAPK activity with SB-203580 dose-dependently inhibits Akt phosphorylation on Ser 473 , but not Thr 308 . Angiotensin II-induced phosphorylation of MAPKAPK-2 is also attenuated by SB-203580, as well as by inhibitors of ROS. In addition, angiotensin II stimulates the association of MAPKAPK-2 with the Aktp38 MAPK complex, and an in vitro kinase assay shows that MAPKAPK-2 immunoprecipitates of VSMC lysates phosphorylate recombinant Akt in an angiotensin II-inducible manner. Finally, intracellular delivery of a MAPKAPK-2 peptide inhibitor blocks Akt phosphorylation on Ser 473 . These results suggest that the p38 MAPK-MAPKAPK-2 pathway mediates Akt activation by angiotensin II in these cells by recruiting active MAPKAPK-2 to a signaling complex that includes both Akt and p38 MAPK. Through this mechanism, p38 MAPK confers ROS sensitivity to Akt and facilitates downstream signaling. These results provide evidence for a novel signaling complex that may help to spatially organize hypertrophy-related, ROSsensitive signaling in VSMCs.mitogen-activated protein kinase; reactive oxygen species ANG II IS A PEPTIDE HORMONE that stimulates a plethora of signaling pathways, leading to cell growth and contraction. On binding to its receptor, the ANG II type 1 receptor, ANG II activates an array of protein kinases important for its growthpromoting effects. These kinases include c-Src (11), epidermal growth factor receptor (8), ERK1/2 (7), p38 MAPK (25), and Akt/protein kinase B (26). Activation of p38 MAPK and Akt requires the production of reactive oxygen species (ROS), whereas ERK1/2 stimulation is independent of ROS (25). Our laboratory has previously shown that all three of these kinases mediate ANG II-induced vascular smooth muscle cell (VSMC) hypertrophy (25,26); however, the relationship between the ROS-sensitive kinases p38 MAPK and Akt is unclear.Although it has been clearly shown that activation of Akt requires phosphatidylinositol 3-kinase (PI3-K) activity and NAD(P)H oxidase-derived production of ROS (6, 26), the full complement of upstream mediators of Akt activation by ANG II is not yet fully understood. Akt activation requires phosphorylation of two amino acid residues by upstream kinases: threonine 308 (Thr 308 ) by 3-phosphoinositide-dependent protein kinase (PDK)-1 and serine 473 (Ser 473 ) by a "so-called" PDK2, whose identity is controversial (4). To date, five kinases have been proposed as candidates for PDK2: Akt itself, PDK1, integrin-linked kinase...

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Section: Discussionmentioning

confidence: 99%

Section: Effect Of P38 Mapk Inhibition On Ang Ii-induced Akt Phosphormentioning

confidence: 99%

Role of p38 MAPK and MAPKAPK-2 in angiotensin II-induced Akt activation in vascular smooth muscle cells

Taniyama¹,

Ushio‐Fukai²,

Hitomi³

et al. 2004

American Journal of Physiology-Cell Physiology

112

View full text Add to dashboard Cite

show abstract

“…The identity of the kinase that phosphorylates the Ser473 site (designated PDK2), however, has been elusive. To date several candidates have been proposed, including integrin-linked kinase (ILK) [96,97], mitogen-activated protein kinase-activated kinase-2 (MAPKAPK-2) [93,98], DNAdependent protein kinase (DNA-PK) [99], and rictor-mTOR complex [100]. Active Akt phosphorylates a large number of substrates, including GSK-3, caspase-9, Bad, MDM2 and Forkhead transcription factors, to mediate its antiapoptotic effects [101].…”

Section: Pkcε: Akting In Concert To Promote Survivalmentioning

confidence: 99%

Protein kinase Cε makes the life and death decision

Basu

Sivaprasad

2007

Cellular Signalling

144

154

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Cancer is caused by dysregulation in cellular signaling systems that control cell proliferation, differentiation and cell death. Protein kinase C (PKC), a family of serine/threonine kinases, plays an important role in the growth factor signal transduction pathway. PKCε, however, is the only PKC isozyme that has been considered as an oncogene. It can contribute to malignancy by enhancing cell proliferation or by inhibiting cell death. This review focuses on how PKCε collaborates with other signaling pathways, such as Ras/Raf/ERK and Akt, to regulate cell survival and cell death. We have also discussed how PKCε mediates is antiapoptotic signal by altering the level or function of proand antiapoptotic Bcl-2 family members.

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“…Phosphoinositide 3-kinase-dependent stimulatory pathways for p38-MAPK and p42/p44-ERK have been described in human neutrophils (34,35). Wortmannin, an inhibitor of phosphoinositide 3-kinase (36), reduced phosphorylation of LSP1 along with the phosphorylation of MAPKAP-K2, p38-MAPK, and p42/p44-ERK in fMLP-stimulated neutrophils.…”

Section: Effects Of Various Inhibitors On the Phosphorylation Of Lsp1mentioning

confidence: 99%

A Stable Aspirin-Triggered Lipoxin A4 Analog Blocks Phosphorylation of Leukocyte-Specific Protein 1 in Human Neutrophils

Ohira

Bannenberg

Arita

et al. 2004

The Journal of Immunology

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Lipoxins and their aspirin-triggered 15-epimers are endogenous anti-inflammatory agents that block neutrophil chemotaxis in vitro and inhibit neutrophil influx in several models of acute inflammation. In this study, we examined the effects of 15-epi-16-(p-fluoro)-phenoxy-lipoxin A4 methyl ester, an aspirin-triggered lipoxin A4-stable analog (ATLa), on the protein phosphorylation pattern of human neutrophils. Neutrophils stimulated with the chemoattractant fMLP were found to exhibit intense phosphorylation of a 55-kDa protein that was blocked by ATLa (10–50 nM). This 55-kDa protein was identified as leukocyte-specific protein 1, a downstream component of the p38-MAPK cascade in neutrophils, by mass spectrometry, Western blotting, and immunoprecipitation experiments. ATLa (50 nM) also reduced phosphorylation/activation of several components of the p38-MAPK pathway in these cells (MAPK kinase 3/MAPK kinase 6, p38-MAPK, MAPK-activated protein kinase-2). These results indicate that ATLa exerts its anti-inflammatory effects, at least in part, by blocking activation of the p38-MAPK cascade in neutrophils, which is known to promote chemotaxis and other proinflammatory responses by these cells.

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p38 Kinase-dependent MAPKAPK-2 Activation Functions as 3-Phosphoinositide-dependent Kinase-2 for Akt in Human Neutrophils

Cited by 253 publications

References 40 publications

Role of p38 MAPK and MAPKAPK-2 in angiotensin II-induced Akt activation in vascular smooth muscle cells

Role of p38 MAPK and MAPKAPK-2 in angiotensin II-induced Akt activation in vascular smooth muscle cells

Protein kinase Cε makes the life and death decision

A Stable Aspirin-Triggered Lipoxin A4 Analog Blocks Phosphorylation of Leukocyte-Specific Protein 1 in Human Neutrophils

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