Cleavage of Fyn and Lyn in their N-terminal unique regions during induction of apoptosis: a new mechanism for Src kinase regulation

Luciano, Fréderic; Ricci, Jean-Ehrland; Auberger, Patrick

doi:10.1038/sj.onc.1204661

Cited by 60 publications

(66 citation statements)

References 45 publications

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“…27 Thus, cleavage of fyn and lyn upon TCR, BCR or Fas triggering could play an important role to block the apoptotic signal in a potential feedback mechanism by relocalization of the soluble forms of these kinases. 25,27 This is consistent with our data that active fyn can protect PIKE-A from apoptotic cleavage and promote cell survival (Figures 4 and 5). When co-transfected with active fynA or srcA, PIKE-A is potently phosphorylated (Figure 2a).…”

Section: Discussionsupporting

confidence: 92%

“…Activation of TCR by immobilized anti-CD3 mAb triggers fyn apoptotic cleavage in T-lymphocytes. 25 Activated T-lymphocytes from the fyn-deficient mice are less sensitive to killing by both anti-Fas antibody and Fas-ligand cytotoxic T cells, 26 indicating that fyn somehow upregulates the programmed cell death in T cells. Interestingly, overexpression in a T-cell hybridoma of a soluble form of fyn lacking the six Nterminal amino acids thus resembling the cleaved form of fyn produced in apoptotic cells inhibits anti-CD3-induced caspase activation and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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Src-family tyrosine kinase fyn phosphorylates phosphatidylinositol 3-kinase enhancer-activating Akt, preventing its apoptotic cleavage and promoting cell survival

Tang

Feng

2006

Cell Death Differ

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Phosphatidylinositol 3-kinase enhancer-activating Akt (PIKE-A) binds Akt and upregulates its kinase activity, preventing apoptosis. PIKE-A can be potently phosphorylated on tyrosine residues 682 and 774, leading to its resistance to caspase cleavage. However, the upstream tyrosine kinases responsible for PIKE-A phosphorylation and subsequent physiological significance remain unknown. Here, we show that PIKE-A can be cleaved by the active apoptosome at both D474 and D592 residues. Employing fyn-deficient mouse embryonic fibroblast cells and tissues, we demonstrate that fyn is essential for phosphorylating PIKE-A and protects it from apoptotic cleavage. Active but not kinase-dead fyn interacts with PIKE-A and phosphorylates it on both Y682 and Y774 residues. Tyrosine phosphorylation in PIKE-A is required for its association with active fyn but not for Akt. Mutation of D into A in PIKE-A protects it from caspase cleavage and promotes cell survival. Thus, this finding provides a molecular mechanism accounting for the antiapoptotic action of src-family tyrosine kinase.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Src-family tyrosine kinase fyn phosphorylates phosphatidylinositol 3-kinase enhancer-activating Akt, preventing its apoptotic cleavage and promoting cell survival

Tang

Feng

2006

Cell Death Differ

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“…The human B lymphoma cell line Ramos (EBVÀ) has been described elsewhere (Luciano et al, 2001). It was grown at 371C under 5% CO 2 in RPMI 1640 medium Phosphorylation of Bim on Ser 69 induces its degradation F Luciano et al supplemented with 10% FCS, 50 mm b-mercaptoethanol and 100 Ug/ml penicillin/streptomycin and chronic myelogenous leukemia cells K562 were grown at 371C under 5% CO 2 in RPMI 1640 medium supplemented with 5% FCS and 100 mg/ml penicillin/streptomycin.…”

Section: Cellsmentioning

confidence: 99%

Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function

et al. 2003

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Bim is a proapoptotic member of the Bcl-2 family that shares only the BH3 domain with this family. Three Bim proteins Bim-EL, Bim-L and Bim-S are synthesized from the same transcript. We report here that Bim-EL when phosphorylated by Erk1/2 is rapidly degraded via the proteasome pathway. Using different cellular models we evidence that serine 69 is both necessary and sufficient for Erk1/2-mediated phosphorylation and degradation of Bim-EL. In K562 cells, Phorbol 12-myristate 13-acetate activates Erk1/2 and consequently increases Bim-EL phosphorylation and degradation by the proteasome, resulting in cell survival, while the Bcr-Abl inhibitor imatinib abrogates Bim-EL phosphorylation and degradation and induces caspase activation and apoptosis. We also show that Bim-EL(S69G) promotes apoptosis more efficiently than Bim-EL-WT in K562 cells. Altogether, our findings demonstrate that phosphorylation of Bim-EL by Erk1/2 on serine 69 selectively leads to its proteasomal degradation and therefore represents a new and important mechanism of Bim regulation.

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“…21 As shown in Figure 2g, treatment of Jurkat cells with CH11 for 8 h led to the disappearance of full-length NEMO (48 kDa) and to the simultaneous rise of a 41 kDa protein recognized by anti-NEMO antibodies (lane 2). We have had difficulties in regularly observing this band, suggesting that it could be unstable or in a disturbed conformational state.…”

Section: Resultsmentioning

confidence: 74%

“…Besides the cleavage of structural proteins, caspases inactivate proteins involved in the transmission of antiapoptotic influences to amplify apoptotic reactions. 19,20 Key examples are protein kinases that transmit activation/survival signals such as fyn, lyn, 21 zap-70, FAK, PKC y and d and Akt. 19 Caspases also target several antiapoptotic proteins endowing some of them such as Bcl-2, Bcl-xl, with apoptotic functions after cleavage.…”

mentioning

confidence: 99%

Inhibition of the NF-κB survival pathway via caspase-dependent cleavage of the IKK complex scaffold protein and NF-κB essential modulator NEMO

et al. 2007

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Apoptosis is mediated by cysteine-dependent, aspartate-directed proteases of the caspase family that proteolyse strategic intracellular substrates to induce cell suicide. We describe here that engagement of apoptotic processes by Fas triggering or by staurosporine stimulation leads to the caspase-dependent inactivation of the nuclear factor kappa B (NF-jB) pathway after cleavage of IKK1 (IjB kinase 1) and NEMO (NF-jB essential modulator), which are needed to transduce NF-jB activation signals. In this study, we have analyzed in more detail, the role of NEMO cleavage, as NEMO, but not IKK1, is important for the prosurvival actions of NF-jB. We demonstrate that NEMO is cleaved after Asp355 to remove the last 64 C-terminal amino acids. This short form was unable to rescue NF-jB activation by tumor necrosis factor-a (TNF-a) when transfected in NEMO-deficient cells. Consequently, inactivation of NEMO resulted in an inhibition of the expression of antiapoptotic NF-jB-target genes coding for caspase inhibitors (cIAP-1, cIAP-2) or adaptors of the TNF receptor family. NEMO-deficient Jurkat cells transiently expressing a non-cleavable mutant of NEMO were less sensitive to TNF-a-induced apoptosis. Therefore, downmodulation of NF-jB activation via the proteolytic cleavage of NEMO could represent an amplification loop for apoptosis.

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Cleavage of Fyn and Lyn in their N-terminal unique regions during induction of apoptosis: a new mechanism for Src kinase regulation

Cited by 60 publications

References 45 publications

Src-family tyrosine kinase fyn phosphorylates phosphatidylinositol 3-kinase enhancer-activating Akt, preventing its apoptotic cleavage and promoting cell survival

Src-family tyrosine kinase fyn phosphorylates phosphatidylinositol 3-kinase enhancer-activating Akt, preventing its apoptotic cleavage and promoting cell survival

Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function

Inhibition of the NF-κB survival pathway via caspase-dependent cleavage of the IKK complex scaffold protein and NF-κB essential modulator NEMO

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