Limits...
Caspase-activated phosphoinositide binding by CNT-1 promotes apoptosis by inhibiting the AKT pathway.

Nakagawa A, Sullivan KD, Xue D - Nat. Struct. Mol. Biol. (2014)

Bottom Line: How this pathway is suppressed to promote apoptosis is poorly understood.Here we report the identification of a CED-3 caspase substrate in Caenorhabditis elegans, CNT-1, that is cleaved during apoptosis to generate an N-terminal phosphoinositide-binding fragment (tCNT-1). tCNT-1 translocates from the cytoplasm to the plasma membrane and blocks AKT binding to phosphatidylinositol (3,4,5)-trisphosphate, thereby disabling AKT activation and its prosurvival activity.Our findings reveal a new mechanism that negatively regulates AKT cell signaling to promote apoptosis and that may restrict cell growth and proliferation in normal cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, Colorado, USA.

ABSTRACT
Inactivation of cell-survival factors is a crucial step in apoptosis. The phosphoinositide 3-kinase (PI3K)-AKT signaling pathway promotes cell growth, proliferation and survival, and its deregulation causes cancer. How this pathway is suppressed to promote apoptosis is poorly understood. Here we report the identification of a CED-3 caspase substrate in Caenorhabditis elegans, CNT-1, that is cleaved during apoptosis to generate an N-terminal phosphoinositide-binding fragment (tCNT-1). tCNT-1 translocates from the cytoplasm to the plasma membrane and blocks AKT binding to phosphatidylinositol (3,4,5)-trisphosphate, thereby disabling AKT activation and its prosurvival activity. Our findings reveal a new mechanism that negatively regulates AKT cell signaling to promote apoptosis and that may restrict cell growth and proliferation in normal cells.

Show MeSH

Related in: MedlinePlus

A model of CED-3-activated suppression of AKT signaling by CNT-1 in C. elegans. In non-apoptotic cells, some AKT kinases are recruited to the plasma membrane and activated by PIP3 to transduce the survival signal. In apoptotic cells, CNT-1 is cleaved by activated CED-3 to generate potent phosphoinositide-binding tCNT-1, which translocates to the plasma membrane from the cytoplasm. tCNT-1 outcompetes AKT kinases for binding to PIP3 and thus displaces and inactivates AKT kinases, leading to loss of the survival signal and apoptosis.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4256149&req=5

Figure 8: A model of CED-3-activated suppression of AKT signaling by CNT-1 in C. elegans. In non-apoptotic cells, some AKT kinases are recruited to the plasma membrane and activated by PIP3 to transduce the survival signal. In apoptotic cells, CNT-1 is cleaved by activated CED-3 to generate potent phosphoinositide-binding tCNT-1, which translocates to the plasma membrane from the cytoplasm. tCNT-1 outcompetes AKT kinases for binding to PIP3 and thus displaces and inactivates AKT kinases, leading to loss of the survival signal and apoptosis.

Mentions: Despite containing a PH domain, a potential phosphoinositide-binding motif, CNT-1 does not bind any phospholipids in vitro or associate with plasma membrane in vivo. Upon activated by CED-3 cleavage during apoptosis, tCNT-1 acquires strong binding to phosphoinositides and translocates to the plasma membrane where it outcompetes AKT kinases for PIP3 binding to block recruitment and activation of AKT kinases at the plasma membrane, thereby inactivating the AKT survival pathway to accelerate cell killing (Fig. 8). Therefore, CED-3 activates a downstream death execution event by cleaving CNT-1, which then inactivates the AKT cell survival pathway. Our study elucidates a previously unknown, regulatory link between cell death execution and cell survival signaling.


Caspase-activated phosphoinositide binding by CNT-1 promotes apoptosis by inhibiting the AKT pathway.

Nakagawa A, Sullivan KD, Xue D - Nat. Struct. Mol. Biol. (2014)

A model of CED-3-activated suppression of AKT signaling by CNT-1 in C. elegans. In non-apoptotic cells, some AKT kinases are recruited to the plasma membrane and activated by PIP3 to transduce the survival signal. In apoptotic cells, CNT-1 is cleaved by activated CED-3 to generate potent phosphoinositide-binding tCNT-1, which translocates to the plasma membrane from the cytoplasm. tCNT-1 outcompetes AKT kinases for binding to PIP3 and thus displaces and inactivates AKT kinases, leading to loss of the survival signal and apoptosis.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4256149&req=5

Figure 8: A model of CED-3-activated suppression of AKT signaling by CNT-1 in C. elegans. In non-apoptotic cells, some AKT kinases are recruited to the plasma membrane and activated by PIP3 to transduce the survival signal. In apoptotic cells, CNT-1 is cleaved by activated CED-3 to generate potent phosphoinositide-binding tCNT-1, which translocates to the plasma membrane from the cytoplasm. tCNT-1 outcompetes AKT kinases for binding to PIP3 and thus displaces and inactivates AKT kinases, leading to loss of the survival signal and apoptosis.
Mentions: Despite containing a PH domain, a potential phosphoinositide-binding motif, CNT-1 does not bind any phospholipids in vitro or associate with plasma membrane in vivo. Upon activated by CED-3 cleavage during apoptosis, tCNT-1 acquires strong binding to phosphoinositides and translocates to the plasma membrane where it outcompetes AKT kinases for PIP3 binding to block recruitment and activation of AKT kinases at the plasma membrane, thereby inactivating the AKT survival pathway to accelerate cell killing (Fig. 8). Therefore, CED-3 activates a downstream death execution event by cleaving CNT-1, which then inactivates the AKT cell survival pathway. Our study elucidates a previously unknown, regulatory link between cell death execution and cell survival signaling.

Bottom Line: How this pathway is suppressed to promote apoptosis is poorly understood.Here we report the identification of a CED-3 caspase substrate in Caenorhabditis elegans, CNT-1, that is cleaved during apoptosis to generate an N-terminal phosphoinositide-binding fragment (tCNT-1). tCNT-1 translocates from the cytoplasm to the plasma membrane and blocks AKT binding to phosphatidylinositol (3,4,5)-trisphosphate, thereby disabling AKT activation and its prosurvival activity.Our findings reveal a new mechanism that negatively regulates AKT cell signaling to promote apoptosis and that may restrict cell growth and proliferation in normal cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, Colorado, USA.

ABSTRACT
Inactivation of cell-survival factors is a crucial step in apoptosis. The phosphoinositide 3-kinase (PI3K)-AKT signaling pathway promotes cell growth, proliferation and survival, and its deregulation causes cancer. How this pathway is suppressed to promote apoptosis is poorly understood. Here we report the identification of a CED-3 caspase substrate in Caenorhabditis elegans, CNT-1, that is cleaved during apoptosis to generate an N-terminal phosphoinositide-binding fragment (tCNT-1). tCNT-1 translocates from the cytoplasm to the plasma membrane and blocks AKT binding to phosphatidylinositol (3,4,5)-trisphosphate, thereby disabling AKT activation and its prosurvival activity. Our findings reveal a new mechanism that negatively regulates AKT cell signaling to promote apoptosis and that may restrict cell growth and proliferation in normal cells.

Show MeSH
Related in: MedlinePlus