Molecular Cloning and Characterization of a New Member of the RAC Protein Kinase Family: Association of the Pleckstrin Homology Domain of 3 Types of RAC Protein Kinase with Protein Kinase C Subspecies and βγ Subunits of G Proteins

Konishi, Hiroaki; Kuroda, S.; Tanaka, Mikiya; Matsuzaki, Hidenori; Ono, Yoshitaka; Kameyama, Kimihiko; Haga, Tatsuya; Kikkawa, Ushio

doi:10.1006/bbrc.1995.2654

Cited by 178 publications

(111 citation statements)

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“…PKB␣, 3 Akt2/PKB␤, and Akt3/PKB␥ (2)(3)(4)(5). Activation of Akt depends on the integrity of the pleckstrin homology (PH) domain, which mediates its membrane translocation, and on the phosphorylation of Thr 308 in the activation loop and Ser 473 (6).…”

mentioning

confidence: 99%

A Small Molecule Inhibits Akt through Direct Binding to Akt and Preventing Akt Membrane Translocation

Kim

Sun

et al. 2010

Journal of Biological Chemistry

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The Akt pathway is frequently hyperactivated in human cancer and functions as a cardinal nodal point for transducing extracellular and intracellular oncogenic signals and, thus, presents an exciting target for molecular therapeutics. Here we report the identification of a small molecule Akt/protein kinase B inhibitor, API-1. Although API-1 is neither an ATP competitor nor substrate mimetic, it binds to pleckstrin homology domain of Akt and blocks Akt membrane translocation. Furthermore, API-1 treatment of cancer cells results in inhibition of the kinase activities and phosphorylation levels of the three members of the Akt family. In contrast, API-1 had no effects on the activities of the upstream Akt activators, phosphatidylinositol 3-kinase, phosphatidylinositol-dependent kinase-1, and mTORC2. Notably, the kinase activity and phosphorylation (e.g. Thr(P) 308 and Ser(P) 473 ) levels of constitutively active Akt, including a naturally occurring mutant AKT1-E17K, were inhibited by API-1. API-1 is selective for Akt and does not inhibit the activation of protein kinase C, serum and glucocorticoid-inducible kinase, protein kinase A, STAT3, ERK1/2, or JNK. The inhibition of Akt by API-1 resulted in induction of cell growth arrest and apoptosis selectively in human cancer cells that harbor constitutively activated Akt. Furthermore, API-1 inhibited tumor growth in nude mice of human cancer cells in which Akt is elevated but not of those cancer cells in which it is not. These data indicate that API-1 directly inhibits Akt through binding to the Akt pleckstrin homology domain and blocking Akt membrane translocation and that API-1 has anti-tumor activity in vitro and in vivo and could be a potential anti-cancer agent for patients whose tumors express hyperactivated Akt.

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mentioning

confidence: 99%

A Small Molecule Inhibits Akt through Direct Binding to Akt and Preventing Akt Membrane Translocation

Kim

Sun

et al. 2010

Journal of Biological Chemistry

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“…However, the tyrosine kinases that phosphorylate PKC isoforms in vivo remain to be identified. Both PKB (26) and PKN (27) have a catalytic domain highly homologous to the PKC family, but were not tyrosine phosphorylated in vitro or in the H 2 O 2 -treated cells (data not shown). Thus, phosphorylation on tyrosine does not appear to be a mechanism of activation commonly observed for protein kinases related to the PKC family.…”

Section: Discussionmentioning

confidence: 96%

Activation of protein kinase C by tyrosine phosphorylation in response to H ₂ O ₂

Konishi

Tanaka

Takemura

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

586

449

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Protein kinase C (PKC) isoforms, ␣, ␤I, and ␥ of cPKC subgroup, ␦ and of nPKC subgroup, and of aPKC subgroup, were tyrosine phosphorylated in COS-7 cells in response to H 2 O 2 . These isoforms isolated from the H 2 O 2 -treated cells showed enhanced enzyme activity to various extents. The enzymes, PKC ␣ and ␦, recovered from the cells were independent of lipid cofactors for their catalytic activity. Analysis of mutated molecules of PKC ␦ showed that tyrosine residues, which are conserved in the catalytic domain of the PKC family, are critical for PKC activation induced by H 2 O 2 . These results suggest that PKC isoforms can be activated through tyrosine phosphorylation in a manner unrelated to receptor-coupled hydrolysis of inositol phospholipids.

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“…PKBβ and PKBγ are approx. 82 % identical with the α-isoform, although PKBγ lacks 23 amino acids at the C-terminus compared with the others [13]. Homologues have also been identified in the nematode worm Caenorhabditis elegans and the fruitfly Drosophila melanogaster, demonstrating wide evolutionary conservation [14,15].…”

Section: Cloning Of Protein Kinase B (C-akt)mentioning

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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Molecular Cloning and Characterization of a New Member of the RAC Protein Kinase Family: Association of the Pleckstrin Homology Domain of 3 Types of RAC Protein Kinase with Protein Kinase C Subspecies and βγ Subunits of G Proteins

Cited by 178 publications

References 0 publications

A Small Molecule Inhibits Akt through Direct Binding to Akt and Preventing Akt Membrane Translocation

A Small Molecule Inhibits Akt through Direct Binding to Akt and Preventing Akt Membrane Translocation

Activation of protein kinase C by tyrosine phosphorylation in response to H ₂ O ₂

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

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Molecular Cloning and Characterization of a New Member of the RAC Protein Kinase Family: Association of the Pleckstrin Homology Domain of 3 Types of RAC Protein Kinase with Protein Kinase C Subspecies and βγ Subunits of G Proteins

Cited by 178 publications

References 0 publications

A Small Molecule Inhibits Akt through Direct Binding to Akt and Preventing Akt Membrane Translocation

A Small Molecule Inhibits Akt through Direct Binding to Akt and Preventing Akt Membrane Translocation

Activation of protein kinase C by tyrosine phosphorylation in response to H 2 O 2

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

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Activation of protein kinase C by tyrosine phosphorylation in response to H ₂ O ₂