3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro

Alessi, Dario R.; Kozlowski, Mark T.; Weng, Qing-Ping; Morrice, Nick; Avruch, Joseph

doi:10.1016/s0960-9822(98)70037-5

Cited by 542 publications

(542 citation statements)

References 27 publications

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“…The binding of pleckstrin homology (PH) domain of PKB/Akt to these phosphoinositides both recruites PKB/Akt to the plasma membrane and in the case of PI(3,4)P2 directly stimulates its kinase activity (Franke et al, 1997a, b). Full activation of PKB/Akt requires phosphorylation of Thr 308 by PDK1 and Ser 473by PDK2 (Alessi et al, 1996(Alessi et al, , 1997. Activated PKB/Akt phosphorylates substrates resulting in a variety of biological e ects including suppression of apoptosis.…”

Section: Role Of Phosphoinositide 3-kinase and Pkb/akt In Anoikismentioning

confidence: 99%

Signaling by integrin receptors

Kumar¹

1998

Oncogene

257

181

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Adhesive interactions are critical for the proliferation, survival and function of all cells. Integrin receptors as the major family of adhesion receptors have been the focus of study for more than a decade. These studies have tremendously enhanced our understanding of the integrin-mediated adhesive interactions and have unraveled novel integrin functions in cell survival mechanisms and in the activation of divergent signaling pathways. The signals from integrin receptors are integrated from those originating from growth factor receptors in order to organize the cytoskeleton, stimulate cell proliferation and rescue cells from matrix detachment-induced programmed cell death. These functions are critical in the regulation of multiple processes such as tissue development, in¯ammation, angiogenesis, tumor cell growth and metastasis and programmed cell death.

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Section: Role Of Phosphoinositide 3-kinase and Pkb/akt In Anoikismentioning

confidence: 99%

Signaling by integrin receptors

Kumar¹

1998

Oncogene

257

181

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“…Localized generation of PIP 3 following receptor-stimulated PI3K activation recruits protein kinase B to the plasma membrane, where it undergoes phosphorylation at threonine 308 and serine 473 by phosphoinositide-dependent kinase (PDK)-1 and a putative PDK2, which are PIP 3 -dependent protein kinases also containing PH domains. This dual phosphorylation reaction results in full activation of protein kinase B [142]. Of interest, PDK1 can also phosphorylate and activate PKCf and -d and p70 S6k , indicating the possibility of a number of interlinked signalling pathways [143].…”

Section: Activation Of Phosphoinositide 3-kinasementioning

confidence: 99%

Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma

Hirst¹,

Walker²,

Chilvers³

2000

Eur Respir J

109

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Chronic persistent asthma is characterized by poorly reversible airflow obstruction and airways inflammation and remodelling. Histopathological studies of airways removed at post mortem from patients with severe asthma reveal marked inflammatory and architectural changes associated with airway wall thickening. Increased airway smooth muscle content, occurring as a result of hyperplastic and/or hypertrophic growth, is believed to be one of the principal contributors to airway wall thickening. In recent years, significant advances have been made in elucidating the mediators and the intracellular pathways that regulate proliferation of airway smooth muscle. The contribution that smooth muscle makes to persistent airflow obstruction may not, however, be limited simply to its increased bulk within the airway wall. Interest is growing in the possibility that reversible phenotypic modulation and increased heterogeneity of airway smooth muscle function may also be a feature of the asthmatic airway. This review focuses on possible mechanisms controlling smooth muscle phenotype heterogeneity as well as on the mediators and intracellular pathways implicated in its cellular proliferation. Particular attention is paid to mechanisms involving activation of the extracellular signal regulated kinase‐, protein kinase C‐ and phosphoinositide 3‐kinase‐dependent pathways, since these appear to be the major candidate second messenger pathways for G protein‐ and tyrosine kinase‐coupled receptor‐stimulated proliferation.

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“…PDK1 has subsequently been shown to phosphorylate and activate a whole group of related protein kinases belonging to the AGC (cAMP-dependent, cGMP-dependent, and protein kinase C) kinase family at their activation, or T-loop site. This includes isoforms of p70 ribosomal S6 kinase (S6K) [4,5], p90 ribosomal S6 kinase (RSK) [6], serum-and glucocorticoid-induced kinase (SGK) [7], conventional [8], novel and atypical [9] isoforms of protein kinase C, and PKC related kinases PRK1 and PRK2 [10]. These protein kinases regulate diverse cellular processes such as proliferation, survival, metabolism and translation.…”

Section: Introductionmentioning

confidence: 99%

Analysis of 3-phosphoinositide-dependent kinase-1 signaling and function in ES cells

Tamgüney

Zhang

Fiedler

et al. 2008

Experimental Cell Research

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Abstract3-Phosphoinositide-dependent kinase-1 (PDK1) phosphorylates and activates several kinases in the cAMP-dependent, cGMP-dependent and protein kinase C(AGC) family. Many putative PDK1 substrates have been identified, but have not been analyzed following transient and specific inhibition of PDK1 activity. Here, we demonstrate that a previously characterized PDK1 inhibitor, BX-795, shows biological effects that are not consistent with PDK1 inhibition. Therefore, we describe the creation and characterization of a PDK1 mutant, L159G, which can bind inhibitor analogues containing bulky groups that hinder access to the ATP binding pocket of wild type (WT) kinases. When expressed in PDK1 −/− ES cells, PDK1 L159G restored phosphorylation of PDK1 targets known to be hypophosphorylated in these cells. Screening of multiple inhibitor analogues showed that 1-NM-PP1 and 3,4-DMB-PP1 optimally inhibited the phosphorylation of PDK1 targets in PDK1 −/− ES cells expressing PDK1 L159G but not WT PDK1. These compounds confirmed previously assumed PDK1 substrates, but revealed distinct dephosphorylation kinetics. While PDK1 inhibition had little effect on cell growth, it sensitized cells to apoptotic stimuli. Furthermore, PDK1 loss abolished growth of allograft tumors. Taken together we describe a model system that allows for acute and reversible inhibition of PDK1 in cells, to probe biochemical and biological consequences.

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3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro

Abstract: PDK1 is one of the components of the signaling pathway recruited by Pl 3-kinase for the activation of p70 S6 kinase as well as of PKB, and serves as a multifunctional effector downstream of the Pl 3-kinase.

Cited by 542 publications

References 27 publications

Signaling by integrin receptors

Signaling by integrin receptors

Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma

Analysis of 3-phosphoinositide-dependent kinase-1 signaling and function in ES cells

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