Activation of RAC-protein kinase by heat shock and hyperosmolarity stress through a pathway independent of phosphatidylinositol 3-kinase.

Konishi, Hiroaki; Matsuzaki, Hidenori; Tanaka, Mikiya; Ono, Yoshitaka; Tokunaga, Chiharu; Kuroda, Shinya; Kikkawa, Ushio

doi:10.1073/pnas.93.15.7639

Cited by 189 publications

(167 citation statements)

References 40 publications

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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%

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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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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].…”

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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“…First, it was shown that Akt is activated by stress signals via mechanisms that are PI3-K-independent (Konishi et al, 1996). More important, the PI3-K-dependent activation of Akt by growth factors was also shown to require phosphorylation (Kohn et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Akt activation by growth factors is a multiple-step process: the role of the PH domain

et al. 1998

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The protein kinase encoded by the Akt proto-oncogene is activated by phospholipid binding, membrane translocation and phosphorylation. To address the relative roles of these mechanisms of Akt activation, we have employed a combination of genetic and pharmacological approaches. Transient transfection of NIH3T3 cells with wild-type Akt, pleckstrin homology (PH) domain mutants, generated on the basis of a PH domain structural model, and phosphorylation site Akt mutants provided evidence for a model of Akt activation consisting of three sequential steps: (1) a PH domain-dependent, growth factor-independent step, marked by constitutive phosphorylation of threonine 450 (T450) and perhaps serine 124 (S124), that renders the protein responsive to subsequent activation events; (2) a growth factor-induced, PI3-K-dependent membrane-translocation step; and (3) a PI3-K-dependent step, characterized by phosphorylation at T308 and S473, that occurs in the cell membrane and is required for activation. When forced to translocate to the membrane, wild-type Akt and PH domain Akt mutants that are defective in the ®rst step become constitutively active, suggesting that the purpose of this step is to prepare the protein for membrane translocation. Both growth factor stimulation and forced membrane translocation, however, failed to activate a T308A mutant. This, combined with the ®nding that T308D/S473D double mutant is constitutively active, suggests that the purpose of the three-step process of Akt activation is the phosphorylation of the protein at T308 and S473. The proposed model provides a framework for a comprehensive understanding of the temporal and spatial requirements for Akt activation by growth factors.

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“…In regard to the upstream regulation of Akt, while the role of PI3-K has well been clari®ed (Franke et al, 1997), a possible involvement of small GTP-binding proteins such as Ras and Rac in IL-3 stimulation of Akt remains obscure. In addition, PI3-K-independent pathway that leads to Akt activation was reported (Konishi et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Anti-apoptotic function of Rac in hematopoietic cells

Nishida¹,

Kaziro²,

Satoh

1999

Oncogene

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The small GTP-binding protein Rac plays a pivotal role in the regulation of diverse physiological events including reorganization of the actin cytoskeleton, cell cycle progression, and transformation. Here we show an anti-apoptotic e ect of Rac in interleukin-3-dependent murine hematopoietic BaF3 cells. Activated Rac(G12V), when ectopically expressed in BaF3 cells, rendered the cells resistant to apoptosis upon interleukin-3 deprivation, while activated mutants of Rho and Cdc42 displayed no signi®cant anti-apoptotic e ect. In contrast to activated Ras, which also supports cell survival in the absence of interleukin-3, Rac required fetal bovine serum for the prevention of cell death. The involvement of phosphatidylinositol 3-kinase downstream of Rac was demonstrated by the inhibition of Rac-induced cell survival by wortmannin and LY294002 and the presence of phosphatidylinositol kinase activity in the Rac immunoprecipitate. Furthermore, the serine/threonine kinase Akt was stimulated by activated Rac and fetal bovine serum in a synergistic manner. Rac-induced Akt activation was mediated by phosphorylation of threonine-308 and serine-473. In addition to the phosphatidylinositol 3-kinase/Akt pathway, the p38 mitogen-activated protein kinase pathway was crucial for Rac-dependent survival, whereas p38 mitogen-activated protein kinase was not implicated in Ras-induced anti-apoptotic signaling. These ®ndings provide evidence for the involvement of Rac in survival signaling of hematopoietic cells.

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Activation of RAC-protein kinase by heat shock and hyperosmolarity stress through a pathway independent of phosphatidylinositol 3-kinase.

Cited by 189 publications

References 40 publications

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

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

Akt activation by growth factors is a multiple-step process: the role of the PH domain

Anti-apoptotic function of Rac in hematopoietic cells

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