Protein Kinase C-θ Mediates a Selective T Cell Survival Signal Via Phosphorylation of BAD

Villalba, Martín; Bushway, Paul J.; Altman, Amnon

doi:10.4049/jimmunol.166.10.5955

Cited by 69 publications

(62 citation statements)

References 55 publications

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“…Direct interaction between PKC⑀ and Bax results in suppression of the proapoptotic activity of Bax (17). Bad phosphorylation induced by either PKC or PKC leads to inactivation of Bad (18,19). All these findings support the notion that Bcl-2 family members potentially function as downstream targets of PKCs in regulating cell survival and cell death.…”

supporting

confidence: 73%

Protein Kinase Cζ Abrogates the Proapoptotic Function of Bax through Phosphorylation

Xin

Gao

May

et al. 2007

Journal of Biological Chemistry

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Protein kinase C (PKC) is an atypical PKC isoform that plays an important role in supporting cell survival but the mechanism(s) involved is not fully understood. Bax is a major member of the Bcl-2 family that is required for apoptotic cell death. Because Bax is extensively co-expressed with PKC in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cells, it is possible that Bax may act as the downstream target of PKC in regulating survival and chemosensitivity of lung cancer cells. Here we discovered that treatment of cells with nicotine not only enhances PKC activity but also results in Bax phosphorylation and prolonged cell survival, which is suppressed by a PKC specific inhibitor (a myristoylated PKC pseudosubstrate peptide). Purified, active PKC directly phosphorylates Bax in vitro. Overexpression of wild type or the constitutively active A119D but not the dominant negative K281W PKC mutant results in Bax phosphorylation at serine 184. PKC co-localizes and interacts with Bax at the BH3 domain. Apoptosis through the mitochondrial pathway is mainly controlled and mediated by Bcl2 family proteins. Bax is a major multidomain proapoptotic member of the Bcl2 family that is required for apoptotic cell death (1). However, the signaling mechanism(s) by which Bax is regulated remains enigmatic. It has been proposed that activation of the proapoptotic function of Bax likely occurs through several interdependent mechanisms including translocation from cytosol to mitochondria (2), oligomerization, and insertion into mitochondrial membranes following stress (3-5). Recent reports indicate that the proapoptotic activity of Bax can also be regulated by phosphorylation, a post-translational modification (6 -9). Growth factor (i.e. granulocyte macrophate-colony-stimulating factor) or survival agonist (i.e. nicotine)-induced Bax phosphorylation at Ser 184 through activation of AKT potently suppresses the proapoptotic activity of Bax and prolongs cell survival (6, 9). In contrast, c-Jun NH 2 -terminal kinase (JNK)-induced Thr 167 or glycogen synthase kinase-induced Ser 163 phosphorylation of Bax may enhance the proapoptotic activity of Bax (7-8). Intriguingly, we recently discovered that protein phosphatase 2A functions as a physiological Bax phosphatase that not only dephosphorylates Bax but also potently activates its proapoptotic function (10).The protein kinase C (PKC) 2 family is a multigene family that can be subclassified into three groups including classical, novel, and atypical PKC isoforms according to differences in the lipid activation profile. The mechanisms for activation have been established for sequential phosphorylation, the recruiting of proper localization, and the exchanging of binding proteins (11). Growing evidence indicates that PKC family members play important roles in regulating cell survival and apoptosis (12)(13)(14)(15). For example, the classic PKC␣-induced Bcl-2 phosphorylation enhances antiapoptotic function of Bcl2 in association with increased chemoresistance of human leu...

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supporting

confidence: 73%

Protein Kinase Cζ Abrogates the Proapoptotic Function of Bax through Phosphorylation

Xin

Gao

May

et al. 2007

Journal of Biological Chemistry

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“…Surprisingly, higher doses of SB202190, which drastically increased JNK activity, were nevertheless found to inhibit megakaryocytic differentiation of K562 and to induce cell death more especially in the presence of PMA. The effect of the combination of PMA and high doses of SB may appear somewhat surprising since PMA has been consistently shown to protect various cell lines against apoptosis (Bertolotto et al, 2000;Villalba et al, 2001;Herrant et al, 2002). However, we have previously established that inhibition of the NFkB pathway, for example, can convert PMA from a death-protecting to a death-inducing function (Busuttil et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

A survey of the signaling pathways involved in megakaryocytic differentiation of the human K562 leukemia cell line by molecular and c-DNA array analysis

et al. 2005

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The K562 cell line serves as a model to study the molecular mechanisms associated with leukemia differentiation. We show here that cotreatment of K562 cells with PMA and low doses of SB202190 (SB), an inhibitor of the p38 MAPK pathway, induced a majority of cells to differentiate towards the megakaryocytic lineage. Electronic microscopy analysis showed that K562 cells treated with PMA þ SB exhibited characteristic features of physiological megakaryocytic differentiation including the presence of vacuoles and demarcation membranes. Differentiation was also accompanied by a net increase in megakaryocytic markers and a reduction of erythroid markers, especially when both effectors were present. PMA effect was selectively mediated by new PKC isoforms. Differentiation of K562 cells by the combination of PMA and SB required Erk1/2 activation, a threshold of JNK activation and p38 MAPK inhibition. Interestingly, higher concentrations of SB, which drastically activated JNK, blocked megakaryocytic differentiation, and considerably increased cell death in the presence of PMA. c-DNA microarray membranes and PCR analysis allow us to identify a set of genes modulated during PMAinduced K562 cell differentiation. Several gene families identified in our screening, including ephrins receptors and some angiogenic factors, had never been reported so far to be regulated during megakaryocytic differentiation.

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“…Moreover, the time frame between the application of the death-inducing stimulus and the first signs of cell death (8 h) appears to be too short to be mediated via the CD95/CD95L-system in primary T cells. Candidate molecules that could connect the TCR to the activation of caspase-3 via the mitochondrial pathway are members of the BH3-only proteins that have been shown to promote apoptosis in T cells for example Bim (32), Bid (33), or Bad (34). Therefore, further work is needed to address which of the BH3-only proteins contribute to Ab-induced apoptosis and how these molecules organize pro-apoptotic pathways after Abmediated apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of Proximal Signaling Events after TCR/CD8-Mediated Induction of Proliferation or Apoptosis in Mature CD8+ T Cells

Wang¹,

Simeoni²,

Lindquist³

et al. 2008

The Journal of Immunology

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Engagement of the TCR can induce different functional outcomes such as activation, proliferation, survival, or apoptosis. How the TCR-mediated signaling cascades generating these distinct cellular responses are organized on the molecular level is so far not completely understood. To obtain insight into this question, we analyzed TCR/CD8-mediated signaling events in mature OT-I TCR transgenic T cells under conditions of stimulation that lead to either proliferation or apoptosis. These experiments revealed major differences in the phosphorylation dynamics of LAT, ZAP70, protein kinase B, phospholipase C-γ1, protein kinase D1, and ERK1/2. Moreover, input signals leading to apoptosis induced a strong, but transient activation of ERK1/2 mainly at sites of TCR-engagement. In contrast, stimuli promoting survival/proliferation generated a low and sustained activation of ERK1/2, which colocalizes with Ras in recycling endosomal vesicles. The transient activation of ERK1/2 under pro-apoptotic conditions of stimulation is at least partially due to the rapid polyubiquitination and subsequent degradation of ZAP70, whereas the sustained activation of ERK1/2 under survival promoting conditions is paralleled by the induction/phosphorylation of anti-apoptotic molecules such as protein kinase B and Bcl-xL. Collectively, our data provide signaling signatures that are associated with proliferation or apoptosis of T cells.

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Protein Kinase C-θ Mediates a Selective T Cell Survival Signal Via Phosphorylation of BAD

Cited by 69 publications

References 55 publications

Protein Kinase Cζ Abrogates the Proapoptotic Function of Bax through Phosphorylation

Protein Kinase Cζ Abrogates the Proapoptotic Function of Bax through Phosphorylation

A survey of the signaling pathways involved in megakaryocytic differentiation of the human K562 leukemia cell line by molecular and c-DNA array analysis

Dynamics of Proximal Signaling Events after TCR/CD8-Mediated Induction of Proliferation or Apoptosis in Mature CD8+ T Cells

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