Phosphorylation of FADD at serine 194 by CKIα regulates its nonapoptotic activities

Elizabeth C. Alappat; Christine Feig; Benjamin Boyerinas; Jörg Volkland; Martin Samuels; Andrea E. Murmann; Andrew Thorburn; Vincent J. Kidd; Clive A. Slaughter; Stephanie L. Osborn; Astar Winoto; Wei Jen Tang; Marcus E. Peter

doi:10.1016/j.molcel.2005.06.024

Phosphorylation of FADD at serine 194 by CKIα regulates its nonapoptotic activities

Elizabeth C. Alappat, Christine Feig, Benjamin Boyerinas, Jörg Volkland, Martin Samuels, Andrea E. Murmann, Andrew Thorburn, Vincent J. Kidd, Clive A. Slaughter, Stephanie L. Osborn, Astar Winoto, Wei Jen Tang, Marcus E. Peter

Research output: Contribution to journal › Article › peer-review

126 Scopus citations

Abstract

FADD is essential for death receptor (DR)-induced apoptosis. However, it is also critical for cell cycle progression and proliferation, activities that are regulated by phosphorylation of its C-terminal Ser194, which has also been implicated in sensitizing cancer cells to chemotherapeutic drugs and in regulating FADD's intracellular localization. We now demonstrate that casein kinase Iα (CKIα) phosphorylates FADD at Ser194 both in vitro and in vivo. FADD-CKIα association regulates the subcellular localization of FADD, and phosphorylated FADD was found to colocalize with CKIα on the spindle poles in metaphase. Inhibition of CKIα diminished FADD phosphorylation, prevented the ability of Taxol to arrest cells in mitosis, and blocked mitogen-induced proliferation of mouse splenocytes. In contrast, a low level of cycling splenocytes from mice expressing FADD with a mutated phosphorylation site was insensitive to CKI inhibition. These data suggest that phosphorylation of FADD by CKI is a crucial event during mitosis.

Original language	English (US)
Pages (from-to)	321-332
Number of pages	12
Journal	Molecular Cell
Volume	19
Issue number	3
DOIs	https://doi.org/10.1016/j.molcel.2005.06.024
State	Published - Aug 5 2005
Externally published	Yes

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.molcel.2005.06.024

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@article{79f98c93e5894bb09f72e2e424b97257,

title = "Phosphorylation of FADD at serine 194 by CKIα regulates its nonapoptotic activities",

abstract = "FADD is essential for death receptor (DR)-induced apoptosis. However, it is also critical for cell cycle progression and proliferation, activities that are regulated by phosphorylation of its C-terminal Ser194, which has also been implicated in sensitizing cancer cells to chemotherapeutic drugs and in regulating FADD's intracellular localization. We now demonstrate that casein kinase Iα (CKIα) phosphorylates FADD at Ser194 both in vitro and in vivo. FADD-CKIα association regulates the subcellular localization of FADD, and phosphorylated FADD was found to colocalize with CKIα on the spindle poles in metaphase. Inhibition of CKIα diminished FADD phosphorylation, prevented the ability of Taxol to arrest cells in mitosis, and blocked mitogen-induced proliferation of mouse splenocytes. In contrast, a low level of cycling splenocytes from mice expressing FADD with a mutated phosphorylation site was insensitive to CKI inhibition. These data suggest that phosphorylation of FADD by CKI is a crucial event during mitosis.",

author = "Alappat, {Elizabeth C.} and Christine Feig and Benjamin Boyerinas and J{\"o}rg Volkland and Martin Samuels and Murmann, {Andrea E.} and Andrew Thorburn and Kidd, {Vincent J.} and Slaughter, {Clive A.} and Osborn, {Stephanie L.} and Astar Winoto and Tang, {Wei Jen} and Peter, {Marcus E.}",

note = "Funding Information: We are grateful to Drs. P. Krammer, C. Liu, B. Seed, G. Shaw, and C. Trautwein for providing reagents. We would like to thank Dr. J. Lahti for critically reading the manuscript and V. Pagala and A. Mishra for help with the mass spec analysis. This work was supported by National Institutes of Health (NIH) grants CA21765-25 (to C.A.S.), CA075162 (to A.W.), and GM044088-13 (to V.J.K.) and generous support from the American Lebanese Syrian Associated Charities (ALSAC). ",

year = "2005",

month = aug,

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doi = "10.1016/j.molcel.2005.06.024",

language = "English (US)",

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pages = "321--332",

journal = "Molecular Cell",

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T1 - Phosphorylation of FADD at serine 194 by CKIα regulates its nonapoptotic activities

AU - Alappat, Elizabeth C.

AU - Feig, Christine

AU - Boyerinas, Benjamin

AU - Volkland, Jörg

AU - Samuels, Martin

AU - Murmann, Andrea E.

AU - Thorburn, Andrew

AU - Kidd, Vincent J.

AU - Slaughter, Clive A.

AU - Osborn, Stephanie L.

AU - Winoto, Astar

AU - Tang, Wei Jen

AU - Peter, Marcus E.

N1 - Funding Information: We are grateful to Drs. P. Krammer, C. Liu, B. Seed, G. Shaw, and C. Trautwein for providing reagents. We would like to thank Dr. J. Lahti for critically reading the manuscript and V. Pagala and A. Mishra for help with the mass spec analysis. This work was supported by National Institutes of Health (NIH) grants CA21765-25 (to C.A.S.), CA075162 (to A.W.), and GM044088-13 (to V.J.K.) and generous support from the American Lebanese Syrian Associated Charities (ALSAC).

PY - 2005/8/5

Y1 - 2005/8/5

N2 - FADD is essential for death receptor (DR)-induced apoptosis. However, it is also critical for cell cycle progression and proliferation, activities that are regulated by phosphorylation of its C-terminal Ser194, which has also been implicated in sensitizing cancer cells to chemotherapeutic drugs and in regulating FADD's intracellular localization. We now demonstrate that casein kinase Iα (CKIα) phosphorylates FADD at Ser194 both in vitro and in vivo. FADD-CKIα association regulates the subcellular localization of FADD, and phosphorylated FADD was found to colocalize with CKIα on the spindle poles in metaphase. Inhibition of CKIα diminished FADD phosphorylation, prevented the ability of Taxol to arrest cells in mitosis, and blocked mitogen-induced proliferation of mouse splenocytes. In contrast, a low level of cycling splenocytes from mice expressing FADD with a mutated phosphorylation site was insensitive to CKI inhibition. These data suggest that phosphorylation of FADD by CKI is a crucial event during mitosis.

AB - FADD is essential for death receptor (DR)-induced apoptosis. However, it is also critical for cell cycle progression and proliferation, activities that are regulated by phosphorylation of its C-terminal Ser194, which has also been implicated in sensitizing cancer cells to chemotherapeutic drugs and in regulating FADD's intracellular localization. We now demonstrate that casein kinase Iα (CKIα) phosphorylates FADD at Ser194 both in vitro and in vivo. FADD-CKIα association regulates the subcellular localization of FADD, and phosphorylated FADD was found to colocalize with CKIα on the spindle poles in metaphase. Inhibition of CKIα diminished FADD phosphorylation, prevented the ability of Taxol to arrest cells in mitosis, and blocked mitogen-induced proliferation of mouse splenocytes. In contrast, a low level of cycling splenocytes from mice expressing FADD with a mutated phosphorylation site was insensitive to CKI inhibition. These data suggest that phosphorylation of FADD by CKI is a crucial event during mitosis.

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JO - Molecular Cell

JF - Molecular Cell

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Phosphorylation of FADD at serine 194 by CKIα regulates its nonapoptotic activities

Abstract

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UN SDGs

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