Enzymes

Enzymes, proteins, riboproteins and signaling pathways.

PDK1

3-Phosphoinositide-dependent protein kinase-1 (PDK1) is a serine /threonine protein kinase that phosphorylates and activates PKB/AKT (Thr308 and Ser473), p70 S6 kinase, p90 ribosomal protein S6 kinase (RSK), PKA, PKC and serum and glucocorticoid-inducible kinase (SGK). (1, 2, 9)

Following stimulation by receptor tyrosine kinases, PI3K is activated and generates the phospholipid second messengers, PtdIns(3,4,5)P 3 and PtdIns(3,4)P 2. These second messengers then emplot diverse mechanisms to mediate the phosphorylation and activation of PDK1 targets (a-st).

Cellular stimulation with pervanadate and IGF-1 results in a significant increase in PDK1 activity and its translocation to the plasma membrane along with increased phosphorylation of tyrosine residues (pk). Phosphorylation on the activation loop at Ser241 alone is necessary for PDK1’s activity and a mutation of single nucleotide (SNP) abolishes its activity (cs).

The phosphatidylinositide-3-OH kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt and the Raf/mitogen-activated protein kinase (MAPK/ERK) kinase (MEK)/mitogen-activated protein kinase (MAPK) pathways play central roles in the regulation of cell survival and proliferation.

Pyruvate dehydrogenase kinase, isoenzyme 1 or 3-phosphoinositide-dependent kinase-1 (PDK1) contains an amino-terminal kinase domain and a carboxyl-terminal pleckstrin homology (PH) domain. PDK1 appears to be conserved throughout evolution (27-31). Although the PDK1 PH domain binds the lipid products of the phosphatidylinositol 3-kinase (PI3K) reaction, binding of these lipids does not alter PDK1 activity, rather it is necessary to localize PDK1 to the plasma membrane. Sphingosine, another biologically active lipid, activates PDK1 toward a variety of substrates (26). It is well established that PDK1 phosphorylates the activation loop (kinase subdomain VIII) of AGC kinase family members p70S6 kinase, Akt, protein kinase A (cAMP-dependent protein kinase), various protein kinase C (PKC) isoforms, and serum- and glucocorticoid-inducible kinases (26, 31, 33-37).(fft-s)

PDK1 promotes MAPK activation in a MEK-dependent manner, and the direct targets of PDK1 in the MAPK pathway are the upstream MAPK kinases MEK1 and MEK2. PDK1 phosphorylation sites in MEK1 and MEK2 are Ser222 and Ser[2][2][6], respectively, and are known to be essential for full activation. PDK1 is associated with maintaining the steady-state phosphorylated MEK level and cell growth. [s] MEK-1 is a dual threonine and tyrosine recognition kinase that phosphorylates and activates mitogen-activated protein kinase (MAPK). MEK-1 is in turn activated by phosphorylation.[1]

Phosphorylated 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates p21-activates kinase 1 (PAK1) in the presence of sphingosine.

Alessi et al. 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Curr Biol. 1997 Oct 1;7(10):776-89.
Stokoe et al. Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science. 1997 Jul 25;277(5325):567-70.
Park J, Hill MM, Hess D, Brazil DP, Hofsteenge J, Hemmings BA. . Identification of tyrosine phosphorylation sites on 3-phosphoinositide-dependent protein kinase-1 and their role in regulating kinase activity. J Biol Chem. 2001 Oct 5;276(40):37459-71. Epub 2001 Jul 31. (Free Full Text Article)
Casamayor A, Morrice NA, Alessi DR. Phosphorylation of Ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1: identification of five sites of phosphorylation in vivo. Biochem J. 1999 Sep 1;342 ( Pt 2):287-92. (Free Full Text Article)

Phosphorylated 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates p21-activates kinase 1 (PAK1) in the presence of sphingosine.
King CC, Gardiner EM, Zenke FT, Bohl BP, Newton AC, Hemmings BA, Bokoch GM.
p21-activated kinase (PAK1) is phosphorylated and activated by 3-phosphoinositide-dependent kinase-1 (PDK1). (Free Full Text Article) J Biol Chem. 2000 Dec 29;275(52):41201-9.

Sphingosine is a novel activator of 3-phosphoinositide-dependent kinase 1. [J Biol Chem. 2000] PMID: 10748151
A GTPase-independent mechanism of p21-activated kinase activation. Regulation by sphingosine and other biologically active lipids. [J Biol Chem. 1998] PMID: 9525917
3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro. [Curr Biol. 1998] PMID: 9427642
Phosphoinositide-dependent kinase 1 and p21-activated protein kinase mediate reactive oxygen species-dependent regulation of platelet-derived growth factor-induced smooth muscle cell migration. [Circ Res. 2004] PMID: 15059930
Evidence that 3-phosphoinositide-dependent protein kinase-1 mediates phosphorylation of p70 S6 kinase in vivo at Thr-412 as well as Thr-252. [J Biol Chem. 1999] PMID: 10601311
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