G-Protein-coupled Receptors and Fcγ-receptors Mediate Activation of Akt/Protein Kinase B in Human Phagocytes

Tilton, Bettina; Andjelković, Mirjana; Didichenko, Svetlana A.; Hemmings, Brian A.; Thelen, Marcus

doi:10.1074/jbc.272.44.28096

Cited by 136 publications

(100 citation statements)

References 71 publications

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“…Akt was shown previously to be activated in human neutrophils by fMLP, leukotriene B4, IL-8, Fc␥R cross-linking, LPS, GM-CSF, and antineutrophil cytoplasmic Abs (18,30,(35)(36)(37). We report for the first time, that a GABA B R agonist, baclofen, stimulates Akt phosphorylation and activation in a PI3K-dependent manner, whereas CGP52432, a GABA B R antagonist inhibits baclofenstimulated Akt activation, suggesting a functional association of Akt and GABA B R in human neutrophils.…”

Section: Discussionmentioning

confidence: 99%

γ-Amino Butyric Acid Type B Receptors Stimulate Neutrophil Chemotaxis during Ischemia-Reperfusion

Rane

Gozal

Butt

et al. 2005

The Journal of Immunology

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Serine/threonine kinase Akt, or protein kinase B, has been shown to regulate a number of neutrophil functions. We sought to identify Akt binding proteins in neutrophils to provide further insights into understanding the mechanism by which Akt regulates various neutrophil functions. Proteomic and immunoprecipitation studies identified γ-amino butyric acid (GABA) type B receptor 2 (GABABR2) as an Akt binding protein in human neutrophils. Neutrophil lysates subjected to Akt immunoprecipitation followed by immunoblotting with anti-GABABR2 demonstrated Akt association with the intact GABABR. Similar results were obtained when reciprocal immunoprecipitations were performed with anti-GABABR2 Ab. Additionally, GABABR2 and Akt colocalization was demonstrated by confocal microscopy. A GABABR agonist, baclofen, activated Akt and stimulated neutrophil-directed migration in a PI3K-dependent manner, whereas CGP52432, a GABABR antagonist blocked such effects. Baclofen, stimulated neutrophil chemotaxis and tubulin reorganization in a PI3K-dependent manner. Additionally, a GABABR agonist failed to stimulate neutrophil superoxide burst. We are unaware of the association of GABABR with Akt in any cell type. The present study shows for the first time that a brain-specific receptor, GABABR2 is present in human neutrophils and that it is functionally associated with Akt. Intraventricular baclofen pretreatment in rats subjected to a stroke model showed increased migration of neutrophils to the ischemic lesion. Thus, the GABABR is functionally expressed in neutrophils, and acts as a chemoattractant receptor via an Akt-dependent pathway. The GABABR potentially plays a significant role in the inflammatory response and neutrophil-dependent ischemia-reperfusion injury such as stroke.

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Section: Discussionmentioning

confidence: 99%

γ-Amino Butyric Acid Type B Receptors Stimulate Neutrophil Chemotaxis during Ischemia-Reperfusion

Rane

Gozal

Butt

et al. 2005

The Journal of Immunology

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“…These studies strongly implicated PKB as a downstream effector of growth-factor-stimulated PI-3K activation in a variety of cell types. Subsequently PKB has been shown to be activated by a wide variety of stimuli including haemopoietic cytokines [IL (interleukin)-2, IL-3, IL-4, IL-5], chemokines [formylmethionylleucylphenylalanine, IL-8, RANTES (regulated on activation, normal T-cell expressed and secreted)], heat shock, hyperosmolarity, hypoxia, integrins, the T-cell antigen receptor and nerve growth factor [32][33][34][35][36][37][38][39][40].…”

Section: Phosphatidylinositol 3-kinase (Pi-3k) Mediates Pkb Activationmentioning

confidence: 99%

“…For example, heat-shock-mediated activation of PKB is insensitive to inhibition by wortmannin in some cell types [32]. Agents which raise intracellular cAMP levels can also activate both PI-3K and PKB activity [38,39]. However, it has been shown in 293 cells that pharmacological reagents that elevate cAMP levels, such as forskolin, can activate PKB in a PI-3K-independent manner [41].…”

Section: Phosphatidylinositol 3-kinase (Pi-3k) Mediates Pkb Activationmentioning

confidence: 99%

Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation

Coffer

Jin

Woodgett

1998

Biochemical Journal

990

818

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While a plethora of extracellular molecules exist that modulate cellular functions via binding to membrane receptors inside the cell, their actions are mediated by relatively few signalling mechanisms. One of these is activation of phosphatidylinositol 3-kinase (PI-3K), which results in the generation of a membranerestricted second messenger, polyphosphatidylinositides containing a 3h-phosphate. How these molecules transduced the effects of agonists of PI-3K was unclear until the recent discovery that several protein kinases become activated upon exposure to 3h-phosphorylated inositol lipids. These enzymes include protein kinase B (PKB)\AKT and PtdIns(3,4,5)P $ -dependent kinases 1 and 2, the first two of which interact with 3h-phosphorylated ORIGINS OF AKTThe AKR strain of mice exhibit a high incidence of leukaemias and lymphomas from spontaneous thymoma [1]. A retrovirus termed AKT8 was isolated from one of these lines derived from a spontaneous thymoma. This virus was demonstrated to uniquely transform only mink lung cells (CCL64) in culture, while virus inoculated into newborn mice was shown to be tumorigenic [2]. The non-viral DNA component transduced from the mouse genome was subsequently identified, and two human homologues, AKT1 and AKT2, cloned [3]. The location of the human AKT locus was mapped to chromosome 14q32, proximal to the immunoglobulin-heavy-chain locus [4], a region frequently affected by translocations and inversions in human Tcell leukaemia\lymphoma, mixed-lineage childhood leukaemia and clonal T-cell proliferations in ataxia telangiectasia, supporting a role for this oncogene in formation of a variety of tumours [5]. Analysis of a panel of human tumours revealed a 20-fold amplification of AKT1 in a primary gastric adenocarcinoma. AKT2, on the other hand, was mapped to chromosome region 19q13.1-q13.2 and shown to be amplified and overexpressed in several ovarian carcinoma and pancreatic cancer cell lines [6,7]. A recent large-scale study of AKT2 alterations in ovarian and breast tumours revealed amplification in 12.1 % ovarian and 2.8 % breast carcinomas [8]. Furthermore, amplification of AKT2 was especially frequent in undifferentiated tumours, suggesting that AKT2 alterations may be associated with tumour aggressiveness.Abbreviations used : PI-3K, phosphatidylinositol 3-kinase ; PKB, protein kinase B ; PKA, protein kinase A ; PKC, protein kinase C ; RAC-PK, related to A-and C-kinase ; PH, pleckstrin homology ; PtdIns, phosphoinositide ; PDGF, platelet-derived growth factor ; EGF, epidermal growth factor ; bFGF, basic fibroblast growth factor ; IL, interleukin ; ERK, extracellular-signal-regulated kinase ; Btk, Bruton tyrosine kinase ; PDK, PtdIns(3,4,5)P 3 -dependent kinase ; MAPKAP, mitogen-activated protein kinase-activated protein ; SH2, Src homology 2 ; gag, group-specific antigen ; GLUT, glucose transporter ; GSK, glycogen synthase kinase ; PFK2, 6-phosphofructose-2-kinase ; IGF, insulin-like growth factor ; 4E-BP1, 4E-binding protein ; PHAS, pH-and acid-stable ; BCR-ABL, breakpoint...

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“…Downstream proteins recruited by the PI3 kinase pathways upon IL-3 stimulation include the PKB/ AKT protein. PI3K-dependent activation of PKB/AKT in response to IL-3 stimulation has been observed in multiple cell lines and these studies suggest a role for this pathway in the transmission of cell survival signals in response to IL-3 (Co er et al, 1998b;Tilton et al, 1997;Songyang et al, 1997;del Peso et al, 1997). Another downstream protein activated in response to IL-3 stimulation is p70S6 kinase which also seems to mediate its e ects via interaction with the b c chain (Sato et al, 1993;Calvo et al, 1994).…”

Section: Pi3k-pkb/akt Pathwaymentioning

confidence: 99%

IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled

et al. 2000

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Hematopoiesis is the cumulative result of intricately regulated signal transduction cascades that are mediated by cytokines and their cognate receptors. Proper culmination of these diverse signaling pathways forms the basis for an orderly generation of di erent cell types and aberrations in these pathways is an underlying cause for diseases such as cancer. Over the past several years, downstream events initiated upon cytokine/ growth factor stimulation have been a major focus of biomedical research. As a result, several key concepts have emerged allowing a better understanding of the complex signaling processes. A group of novel transcription factors, termed signal transducers and activators of transcription (STATs) appear to orchestrate the downstream events propagated by cytokine/growth factor interactions with their cognate receptors. Until recently, the JAK proteins were considered to be the tyrosine kinases, which dictated the levels of phosphorylation and activation of STAT proteins, forming the basis of the JAK-STAT model. However, over the past few years, increasing evidence has accumulated which indicates that at least some of the STAT protein activation may be mediated by members of the Src gene family following cytokine/growth factor stimulation. Studies have demonstrated that the Src-family of tyrosine kinases can phosphorylate and activate certain STAT proteins, in lieu of JAK kinases. In such a scenario, JAK kinases may be more crucial to phosphorylation of the cytokine/growth factor receptors and in the process create docking sites on the receptors for binding of SH2-containing proteins such as STATs, Src-kinases and other signaling intermediates. Tyrosine phosphorylation and activation of STAT proteins can be achieved either by JAKs or Src-kinases depending on the nature of STAT that is being activated. This forms the basis for the JAK-Src-STAT model proposed in this review. The concerted action of JAK kinases, members of the Src-kinase family and STAT proteins, leads to cell proliferation and cell survival, the end-point of the cytokine/growth factor stimulus.

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G-Protein-coupled Receptors and Fcγ-receptors Mediate Activation of Akt/Protein Kinase B in Human Phagocytes

Cited by 136 publications

References 71 publications

γ-Amino Butyric Acid Type B Receptors Stimulate Neutrophil Chemotaxis during Ischemia-Reperfusion

γ-Amino Butyric Acid Type B Receptors Stimulate Neutrophil Chemotaxis during Ischemia-Reperfusion

Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation

IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled

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