p21-activated Kinase (PAK1) Is Phosphorylated and Activated by 3-Phosphoinositide-dependent Kinase-1 (PDK1)

King, Charles C.; Gardiner, Elisabeth; Zenke, Frank T.; Bohl, Benjamin P.; Newton, Alexandra C.; Hemmings, Brian A.; Bokoch, Gary M.

doi:10.1074/jbc.m006553200

Cited by 222 publications

(188 citation statements)

References 53 publications

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“…Both Fra-1 and Runx2 are known downstream targets of the Wnt or cat/TCF signaling pathway (Mann et al, 1999;Dong et al, 2006). In this study, we found that insulin stimulates PAK-1 phosphorylation/activation in multiple cancer cell lines and in mouse intestinal tissues on Thr423, a target residue of phosphoinositide-dependent kinase isozyme-1, hence bypassing Akt (King et al, 2000). We have also found that PAK-1 knockdown significantly reduced insulin-stimulated c-Myc and cyclin D1 expression, as well as cell growth, and completely blocked the insulinstimulated interaction between b-cat and the c-Myc gene promoter.…”

Section: Discussionmentioning

confidence: 60%

“…PAK-1 was initially recognized as a downstream target of the Rho family GTPases, Rac1 and Cdc42, in regulating actin remodeling (Knaus and Bokoch, 1998;Zhou and Field, 2004;Arias-Romero and Chernoff, 2008). PAK-1 can also be activated by Akt (Zhou et al, 2003), or become directly phosphorylated/activated by PI3K (Tsakiridis et al, 1996) or phosphoinositide-dependent kinase isozyme-1 on Thr 423 (King et al, 2000), without requiring Akt. In this study, we show that insulin stimulates the phosphorylation/activation of PAK-1 in both intestinal cancer and non-cancer cell lines, and in several mouse tissues, including the intestines.…”

Section: Introductionmentioning

confidence: 99%

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P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine

et al. 2009

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Hyperinsulinemia and type II diabetes are associated with an increased risk of developing colorectal tumors. We found previously that in intestinal cells, insulin or insulinlike growth factor-1 stimulates c-Myc and cyclin D1 protein expression through both Akt-dependent and Aktindependent mechanisms. The effect of Akt is attributed to the stimulation of c-Myc translation by mammalian target of rapamycin. However, Akt-independent stimulation was, associated with an increase in b-catenin (b-cat) in the nucleus and an increased association between b-cat and T-cell factor binding sites on the c-Myc promoter, detected by chromatin immunoprecipitation. In this study, we show that insulin stimulated the phosphorylation/ activation of p-21-activated protein kinase-1 (PAK-1) in an Akt-independent manner in vitro and in an in vivo hyperinsulinemic mouse model. Significantly, shRNA (small hairpin RNA)-mediated PAK-1 knockdown attenuated both basal and insulin-stimulated c-Myc and cyclin D1 expression, associated with a marked reduction in extracellular signal-regulated kinase activation and b-cat phosphorylation at Ser675. Furthermore, PAK-1 silencing led to a complete blockade of insulin-stimulated b-cat binding to the c-Myc promoter and cellular growth. Finally, inhibition of MEK, a downstream target of PAK-1, blocked insulin-stimulated nuclear b-cat accumulation and c-Myc expression. Our observations suggest that PAK-1 serves as an important linker between insulin and Wnt signaling pathways.

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Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine

et al. 2009

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“…33 However, perifosine did not affect the levels of Ser 241 p-PDK-1, in agreement with the observations of others 17,34 (Figure 3a). As a further proof that perifosine does not negatively affect PDK-1 activity, the phosphorylation state of Thr 423 PAK-1, a downstream target of Perifosine-mediated cytotoxicity in AML V Papa et al PDK-1, 35 was analyzed. Consistently, the drug did not change the levels of Thr 423 p-PAK-1 (Figure 3a).…”

Section: Perifosine Negatively Affects Cell Survival and Induces Apopmentioning

confidence: 99%

Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells

et al. 2007

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The serine/threonine kinase Akt, a downstream effector of phosphatidylinositol 3-kinase (PI3K), is known to play an important role in antiapoptotic signaling and has been implicated in the aggressiveness of a number of different human cancers including acute myelogenous leukemia (AML). We have investigated the therapeutic potential of the novel Akt inhibitor, perifosine, on human AML cells. Perifosine is a synthetic alkylphospholipid, a new class of antitumor agents, which target plasma membrane and inhibit signal transduction networks. Perifosine was tested on THP-1 and MV 4-11 cell lines, as well as primary leukemia cells. Perifosine treatment induced cell death by apoptosis in AML cell lines. Perifosine caused Akt and ERK 1/2 dephosphorylation as well as caspase activation. In THP-1 cells, the proapoptotic effect of perifosine was partly dependent on the Fas/FasL system and c-jun-N-kinase activation. In MV 4-11 cells, perifosine downregulated phosphorylated Akt, but not phosphorylated FLT3. Moreover, perifosine reduced the clonogenic activity of AML, but not normal, CD34 þ cells, and markedly increased blast cell sensitivity to etoposide. Our findings indicate that perifosine, either alone or in combination with existing drugs, might be a promising therapeutic agent for the treatment of those AML cases characterized by upregulation of the PI3K-Akt survival pathway.

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“…The GEF integrates G i␤␥ and PIP 3 signals to activate Rac1, which couples directly to PAK2 and cell migration. PAKs including PAK2 are believed to become autophosphorylated on Thr and Ser residues upon activation, but an alternative phosphorylation mechanism by PDK1 has also been described (42). CSF-1 activates class I A PI3Ks and PAK2 by a mechanism that might involve Rho-GTPases other than Rac (not shown in the model).…”

Section: Pi3k␥-dependent and Pi3k-independent G I -Mediated Activatiomentioning

confidence: 99%

“…Active Rac GTP precipitated by PAK-PBD was separated on SDS-PAGE, transferred to nitrocellulose membrane, and blotted for pan-Rac, followed by ECL detection. Left lanes, the total signal detected using cytosol preloaded with Chemokine-induced PI3K␥-Rac-Pak Signaling 43276 loop of the kinase domain and is known to be required for activation (41)(42)(43). The phospho-PAK Thr antibody demonstrated that RANTES stimulation of macrophages for 10 and 30 s triggered phosphorylation of PAK2 Thr-402 , but less so in PI3K␥Ϫ/Ϫ BMDM (Fig.…”

Section: Rantes-induced Rac Activationmentioning

confidence: 99%

Involvement of Phosphoinositide 3-Kinase γ, Rac, and PAK Signaling in Chemokine-induced Macrophage Migration

Weiss-Haljiti

Pasquali

et al. 2004

Journal of Biological Chemistry

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In macrophages, chemotactic stimuli cause the activation of Rac and PAK, but little is known about the signaling pathways involved and their role in chemotactic gradient sensing. Herein, we report that in macrophages, the chemokine RANTES (regulated on activation normal T cell expressed and secreted)/CCL5 activates the small GTPase Rac and its downstream target PAK2 within seconds. This response depends on G i activation and largely on the subsequent triggering of phosphoinositide 3-kinase ␥ (PI3K␥) and Rac. Retroviral transduction of tagged Rac1 and -2 indicates that RAN-TES/CCL5-mediated activation of PI3K␥ triggers Rac1 but not Rac2. In agreement, silencing of Rac1 by shRNA blocks PAK2 activity and inhibits RANTES/CCL5-induced macrophage polarization and directional migration. On the other hand, the tyrosine kinase receptor agonist CSF-1 activates PAK2 independently of PI3K␥ and Rac. Our results thus demonstrate a chemokinespecific signaling pathway in which G i and PI3K␥ coordinate to drive Rac1 and PAK2 activation that eventually controls the chemotactic response.Rac1, Rac2, and Rac3 constitute a subfamily of the Rho family of monomeric GTPases and cycle between active GTP-bound (Rac GTP ) and inactive GDP-bound (Rac GDP ) states (1-3). Activation is accomplished by guanine-nucleotide exchange factors (GEFs), 1 which catalyze GDP dissociation (4), and inactivation by GTPase-activating proteins, which increase the intrinsic GTPase activity (5). Rho GTPases integrate signals from cellular receptors and membrane components to regulate the cytoskeleton dynamics required for cell locomotion during chemotaxis, phagocytosis, and many other cellular responses (2, 6).Leukocyte chemotaxis toward sites of inflammation (7) is primarily mediated by chemokine signaling. RANTES CCL5 is a disease-relevant and potent chemoattractant for macrophages. Moreover, it has been shown that RANTES-mediated T-cell activation and chemotaxis requires Rho GTPase activity (8,9). RANTES is a member of the CC-subfamily of chemokines and activates the seven-transmembrane CC-chemokine receptors CCR1, CCR3, CCR4, and CCR5, which are coupled to pertussis toxin sensitive heterotrimeric G i␣ proteins (10). PI3K was identified as a target of these G-protein-coupled chemokine receptors because chemotaxis and polarization of T cells could be inhibited by isoform non-selective class I PI3K inhibitors, such as LY294002 (11). All class I PI3Ks are heterodimers consisting of a 110-kDa (p110) catalytic subunit and an 85-(p85) or 101-kDa (p101) regulatory subunit (12). The two catalytic subunits p110␣ and -␤ are ubiquitously expressed, whereas p110␥ and -␦ expression is largely confined to leukocytes. In addition to their characteristic expression, PI3Ks are differentially regulated by GPCRs and receptor tyrosine kinases (RTKs) (13). RTKs have been shown to activate p110␣, -␤, and -␦ via the p85 regulatory subunit (class I A: PI3K-␣, -␤, and -␦). In contrast, it has been shown that regulation of p110␥ (class I B: PI3K␥) is mediated via the p101 adapter, ...

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p21-activated Kinase (PAK1) Is Phosphorylated and Activated by 3-Phosphoinositide-dependent Kinase-1 (PDK1)

Cited by 222 publications

References 53 publications

P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine

P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine

Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells

Involvement of Phosphoinositide 3-Kinase γ, Rac, and PAK Signaling in Chemokine-induced Macrophage Migration

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