Scaffolding function of PAK in the PDK1–Akt pathway

Higuchi, Masakazu; Onishi, Kiyoshi; Kikuchi, Chikako; Gotoh, Yukiko

doi:10.1038/ncb1795

Cited by 201 publications

(207 citation statements)

References 30 publications

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“…Partial inhibition of Pak activity by PAK18 did not alter Akt activation, which may be due to a kinase-independent mode of Akt activation by Pak as reported recently (Higuchi et al, 2008). The preferential control of Mek activation by Pak1 and of Akt activation by Pak2 suggests that cell type-specific expression of Pak1 and Pak2 will result in cell type-specific effects of Rac1 on Mek1 and Akt, respectively.…”

Section: Rac1 In Skin Tumorssupporting

confidence: 71%

“…Rac1 was reported to promote RafMek-Erk signaling by Pak-mediated phosphorylation of Raf at serine 338 (King et al, 1998), or of Mek1 at serine 298 (Slack-Davis et al, 2003), by promoting interaction between Mek and Erk (Eblen et al, 2002), by direct interaction of Rac1 with Erk (Sundberg-Smith et al, 2005) and by controlling the nuclear translocation of Erk (Hirsch et al, 2002). With respect to PI3K signaling, Rac1 was shown to be upstream (Keely et al, 1997) and downstream of PI3K signaling (Hawkins et al, 1995), and the Rac1 effector, Pak1, was shown to activate Akt by direct interaction, independent of the kinase function of Pak (Higuchi et al, 2008). However, although Rac1 activation was found to promote cell survival by activation of Akt, Erk and NF-kB, it can also induce apoptosis by stimulation of p38 and JNK (Xia et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation in vivo

et al. 2010

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Rac1 has a role in proliferation and survival of tumor cells in vitro. The exact effects of Rac1 on growth, apoptosis and corresponding signaling pathways during tumorigenesis in vivo, however, have not been explored yet. Using mice with a keratinocyte-restricted deletion of the Rac1 gene, we found that Rac1 is essential for DMBA/TPAinduced skin tumor formation. This corresponded to a decreased keratinocyte hyperproliferation, although apoptosis was not detectably altered. Activated Rac1 promoted Erk-dependent hyperproliferation by Pak1-mediated Mek activation independent of Mek1 phosporylation at serine 298. Rac1 was furthermore required for Pak2-dependent hyperactivation of Akt, which under in vivo condition was restricted to the suprabasal cell layers corresponding to a suprabasal-specific expression of Pak2. It is surprising that none of these signaling pathways was altered in untreated Rac1-deficient skin, indicating a hyperproliferation-specific function of Rac1 in vivo. These data suggest that blocking of Rac1 function might allow tumor-specific growth repression, as Rac1 is not required for normal growth and growth signaling controlling pathways in skin in vivo.

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Section: Rac1 In Skin Tumorssupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation in vivo

et al. 2010

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“…It has been reported that Rac1 stimulates Akt activity through a kinase-independent scaffolding function of PAK1 34 . We then assessed the possible involvement of PAK1 in blebbistatininduced Akt activation.…”

Section: Nature Communications | Doimentioning

confidence: 99%

“…We then assessed the possible involvement of PAK1 in blebbistatininduced Akt activation. PAK1(N-SP) (the N-terminal fragment of PAK1, 1-205aa, with the substitution of Ser76 with proline), a dominant-negative mutant disrupting the scaffolding function of PAK1 34 , effectively abolished the effect of blebbistatin to activate Akt (Fig. 4g).…”

Section: Nature Communications | Doimentioning

confidence: 99%

The non-muscle-myosin-II heavy chain Myh9 mediates colitis-induced epithelium injury by restricting Lgr5+ stem cells

Zhao

et al. 2015

Nat Commun

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Lgr5 þ stem cells are crucial to gut epithelium homeostasis, and therapies targeting these cells hold promise for treatment of gastrointestinal diseases. Here we report that the non-muscle-myosin-II (NMII) heavy chain Myh9 accumulates at epithelial injury sites in mice distal colon treated with dextran sulphate sodium (DSS). Gut-epithelium-specific Myh9 monoallelic deletion alleviates DSS-induced colonic crypt damage and acute colitis. Consistently, the NMII inhibitor blebbistatin can improve the survival of Lgr5 þ stem cells and the growth of Lgr5 organoids. Mechanistically, inhibition of NMII by blebbistatin or Myh9 monoallelic deletion activates Akt through Rac1 and PAK1, which is essential for the survival and pluripotency of Lgr5 þ cells. These results establish a critical role of the Myh9-Rac1-PAK1-Akt pathway in the maintenance of Lgr5 þ stem cells. As blebbistatin can mitigate DSS-induced colitis and preserve Lgr5 þ colonic stem cells in vivo, our findings provide a potential therapeutic intervention of gastrointestinal epithelium injury and degenerative diseases.

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“…An attractive hypothesis is the existence of cofactors working in conjunction with TM phosphorylation. Akt-binding proteins, such as Hsp90 (Sato et al, 2000;Basso et al, 2002), TRB3 and PAK (Du et al, 2003;Du and Tsichlis, 2005;Higuchi et al, 2008), have been reported to regulate negatively or positively the phosphorylation status of Akt. It would be interesting to evaluate the relationship between their binding ability and TM phosphorylation.…”

Section: Regulation Of A-loop Phosphorylation Via Tm Phosphorylation mentioning

confidence: 99%

Turn motif phosphorylation negatively regulates activation loop phosphorylation in Akt

2011

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Akt, also known as protein kinase B, has a central role in various signaling pathways that regulate cellular processes such as metabolism, proliferation and survival. On stimulation, phosphorylation of the activation loop (Aloop) and hydrophobic motif (HM) of Akt by the kinase phosphoinositide-dependent kinase 1 (PDK1) and the mammalian target of rapamycin complex 2 (mTORC2), respectively, results in Akt activation. A well-conserved threonine in the turn motif (TM) is also constitutively phosphorylated by mTORC2 and contributes to the stability of Akt. The role of TM phosphorylation in HM and A-loop phosphorylation has not been sufficiently evaluated. Using starfish oocytes as a model system, this study provides the first evidence that TM phosphorylation has a negative role in A-loop phosphorylation. In this system, the maturation-inducing hormone, 1-methyladenine, stimulates Akt to reinitiate meiosis through activation of cyclin B-Cdc2. The phosphorylation status of Akt was monitored via introduction of exogenous human Akt (hAkt) in starfish oocytes. TM and HM phosphorylation was inhibited by microinjection of an anti-starfish TOR antibody, but not by rapamycin treatment, suggesting that both phosphorylation events depend on TORC2, as reported in mammalian cells. A single or double alanine substitution at each of three phosphorylation residues revealed that TM phosphorylation renders Akt susceptible to dephosphorylation on the A-loop. When A-loop phosphatase was inhibited by okadaic acid (OA), TM phosphorylation still reduced Aloop phosphorylation, suggesting that the effect is caused at least partially through reduction of sensitivity to PDK1. Negative regulation by TM phosphorylation was also observed in constitutively active Akt and was functionally reflected in meiosis resumption. By contrast, HM phosphorylation enhanced A-loop phosphorylation and achieved full activation of Akt via a mechanism at least partially independent of TM phosphorylation. These observations provide new insight into the mechanism controlling Akt phosphorylation in the cell.

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Scaffolding function of PAK in the PDK1–Akt pathway

Cited by 201 publications

References 30 publications

Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation in vivo

Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation in vivo

The non-muscle-myosin-II heavy chain Myh9 mediates colitis-induced epithelium injury by restricting Lgr5+ stem cells

Turn motif phosphorylation negatively regulates activation loop phosphorylation in Akt

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