Modulation of specific protein expression levels by PTEN: identification of AKAP121, DHFR, G3BP, Rap1 and RCC1 as potential targets of PTEN

Huang, Yanping; Wernyj, Roman; Norton, Darrell D.; Precht, Patricia; Seminario, Maria-Cristina; Wange, Ronald L.

doi:10.1038/sj.onc.1208527

Cited by 22 publications

(22 citation statements)

References 41 publications

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“…7C). This would be consistent with recent reports demonstrating selective regulation of protein stability by PTEN (13) and Akt (33). We are currently assessing this possibility.…”

Section: Discussionsupporting

confidence: 78%

CARMA1 Is Required for Akt-Mediated NF-κB Activation in T Cells

Narayan

Holt

Tosti

et al. 2006

Molecular and Cellular Biology

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Many details of the generic pathway for induction of NF-B have been delineated, but it is still not clear how multiple, diverse receptor systems are able to converge on this evolutionarily conserved family of transcription factors. Recent studies have shown that the CARMA1, Bcl10, and MALT1 proteins are critical for coupling the common elements of the NF-B pathway to the T-cell receptor (TCR) and CD28. We previously demonstrated a role for the serine/threonine kinase Akt in CD28-mediated NF-B induction. Using a CARMA1-deficient T-cell line, we have now found that the CARMA complex is required for induction of NF-B by Akt, in cooperation with protein kinase C activation. Furthermore, using a novel selective inhibitor of Akt, we confirm that Akt plays a modulatory role in NF-B induction by the TCR and CD28. Finally, we provide evidence for a physical and functional interaction between Akt and CARMA and for Akt-dependent phosphorylation of Bcl10. Therefore, in T cells, Akt impinges upon NF-B signaling through at least two separate mechanisms.Inducible activation of transcription through the NF-B family of factors is essential for the regulation of many immune response genes (19,27). Some of the best characterized of these include the cytokine interleukin 2 (IL-2), the alpha chain of its high-affinity receptor, and the prosurvival molecule Bcl-x L . NF-B can be induced by signals from the T-cell receptor (TCR)/CD3 complex and the costimulatory receptor CD28. Study of the signaling pathways used by receptors for proinflammatory cytokines, such as tumor necrosis factor (TNF), has revealed a common pathway used by most, if not all, receptors to induce NF-B (24). Access of NF-B transcription factor dimers to the nucleus is controlled by inducible degradation of an inhibitory protein known as IB, which normally sequesters NF-B in the cytoplasm. IB degradation occurs after its inducible phosphorylation, which results in ubiquitination and degradation by the proteasome. Phosphorylation is catalyzed by a trimeric complex that includes two catalytic subunits, IB kinase ␣ (IKK␣) and IKK␤, and an adaptor subunit, IKK␥. Another level of NF-B regulation involves phosphorylation or acetylation of the NF-B proteins themselves (6).

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“…7C). This would be consistent with recent reports demonstrating selective regulation of protein stability by PTEN (13) and Akt (33). We are currently assessing this possibility.…”

Section: Discussionsupporting

confidence: 78%

CARMA1 Is Required for Akt-Mediated NF-κB Activation in T Cells

Narayan

Holt

Tosti

et al. 2006

Molecular and Cellular Biology

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“…Finally, it has been shown that PTEN interacts with a variety of molecules that have been associated with cell growth, apoptosis, and cell cycle control (33,34). Studies designed to define the PTEN interactome in response to ␣2␤1 integrin-type I collagen interaction will probably shed further light on the mechanism by which collagen matrix contraction modulates PTEN activity.…”

Section: Discussionmentioning

confidence: 99%

PTEN Regulates Fibroblast Elimination during Collagen Matrix Contraction

Nho

Xia

Diebold

et al. 2006

Journal of Biological Chemistry

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During tissue repair, excess fibroblasts are eliminated by apoptosis. This physiologic process limits fibrosis and restores normal anatomic patterns. Replicating physiologic apoptosis associated with tissue repair, fibroblasts incorporated into type I collagen matrices undergo apoptosis in response to collagen matrix contraction. In this in vitro model of wound repair, fibroblasts first attach to collagen via ␣2␤1 integrin. This provides a survival signal via activation of the phosphatidylinositol 3-kinase/Akt signal pathway. However, during subsequent collagen matrix contraction, the level of phosphorylated Akt progressively declines, triggering apoptosis. The mechanism underlying the fall in phosphorylated Akt is incompletely understood. Here we show that PTEN phosphatase becomes activated during collagen matrix contraction and is responsible for antagonizing phosphatidylinositol 3-kinase activity and promoting a decline in phosphorylated Akt and fibroblast apoptosis in response to collagen contraction. PTEN null fibroblasts displayed enhanced levels of phosphorylated Akt and were resistant to collagen matrix contraction-induced apoptosis. Reconstitution of PTEN in PTEN null cells conferred susceptibility to apoptosis in response to contraction of collagen matrices. Consistent with this, knockdown of PTEN in PTEN ؉/؉ embryonic fibroblasts by small interfering RNA augmented Akt activity and suppressed apoptosis in contractile collagen matrices. Furthermore, inhibition of Akt activity restored the sensitivity of PTEN null cells to collagen contraction-induced apoptosis, indicating that the mechanism by which PTEN alters fibroblast viability is through modulation of phosphorylated Akt levels. Our work suggests that collagen matrix contraction activates PTEN by a mechanism involving cytoskeletal disassembly. Our studies indicate a key role for PTEN in regulating fibroblast viability during tissue repair.Fibroblasts play an essential role in tissue repair. In response to injury, interstitial fibroblasts differentiate into myofibroblasts (1). Myofibroblasts synthesize and deposit type I collagen into the wound provisional matrix (2). They subsequently contract the type I collagen matrix, facilitating wound closure (3, 4).Following contraction of the type I collagen matrix, myofibroblasts are eliminated by apoptosis, reducing wound cellularity (3). The precise molecular mechanisms governing removal of fibroblasts during tissue repair are unclear.Using fibroblasts cultured in three-dimensional contractile type I collagen matrices as a model of wound/tissue repair, the molecular signals regulating fibroblast viability during collagen contraction have begun to be elucidated. When fibroblasts are incorporated into the type I collagen matrix, they utilize ␣2␤1 integrin to attach and spread (5). This results in phosphorylation of serine 473 of Akt. Activation of Akt provides a survival signal that is mediated through phosphatidylinositol 3-kinase (PI3K) 3 (5-12). However, upon collagen matrix contraction, this integrin sur...

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“…Upregulation of G3BP1 was noted in PTEN-null human cells, whereas overexpression of PTEN suppressed G3BP1 expression. Furthermore, the negative effect of PTEN expression on G3BP1 protein levels was recapitulated by direct inhibition of PI3 kinase activity (Huang et al, 2005). G3BP1 levels have also been shown to increase in response to heregulin in human Her2-positive breast cancer cells (Barnes et al, 2002).…”

Section: Introductionmentioning

confidence: 99%