Wnt signaling inhibits casein kinase 1α activity by modulating its interaction with protein phosphatase 2A
Summary: The mechanism by which Wnt signaling, an essential pathway controlling development and disease, stabilizes β-catenin has been a subject of debate over the last four decades. Casein kinase 1α (CK1α) functions as a pivotal negative regulator of this signaling pathway, initiating the events th...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725000452 |
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| author | Chen Shen Wenhui Lu Siva B. Merugu Aradhana Bharti Said M. Afify Lauren Schnitkey Daniel T. Wynn Fan Yang Thomas M. Rohwetter Anmada Nayak Nawat Bunnag Carolina Cywiak Hsin-Yao Tang Brent T. Harris Christopher Albanese Chukwuemeka Ihemelandu Melanie H. Cobb Arminja Kettenbach Ethan Lee Yashi Ahmed David J. Robbins |
| author_facet | Chen Shen Wenhui Lu Siva B. Merugu Aradhana Bharti Said M. Afify Lauren Schnitkey Daniel T. Wynn Fan Yang Thomas M. Rohwetter Anmada Nayak Nawat Bunnag Carolina Cywiak Hsin-Yao Tang Brent T. Harris Christopher Albanese Chukwuemeka Ihemelandu Melanie H. Cobb Arminja Kettenbach Ethan Lee Yashi Ahmed David J. Robbins |
| author_sort | Chen Shen |
| collection | DOAJ |
| description | Summary: The mechanism by which Wnt signaling, an essential pathway controlling development and disease, stabilizes β-catenin has been a subject of debate over the last four decades. Casein kinase 1α (CK1α) functions as a pivotal negative regulator of this signaling pathway, initiating the events that destabilize β-catenin. However, whether and how CK1α activity is regulated in Wnt-off and Wnt-on states remains poorly understood. We now show that CK1α activity requires its association with the α catalytic subunit of protein phosphatase 2A (PPP2CA) on AXIN, the scaffold protein of the β-catenin destruction complex. Wnt stimulation induces the dissociation of PPP2CA from CK1α, resulting in CK1α autophosphorylation and its consequent inactivation. Moreover, autophosphorylated CK1α is enriched in a subset of colorectal cancers (CRCs) harboring constitutive Wnt activation. Our findings identify a mechanism by which Wnt stimulation inactivates CK1α, filling a critical gap in our understanding of Wnt signaling, with relevance for CRC. |
| format | Article |
| id | doaj-art-d473d7121e4f4c8280afa95925eb9aff |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-d473d7121e4f4c8280afa95925eb9aff2025-02-06T05:11:32ZengElsevierCell Reports2211-12472025-02-01442115274Wnt signaling inhibits casein kinase 1α activity by modulating its interaction with protein phosphatase 2AChen Shen0Wenhui Lu1Siva B. Merugu2Aradhana Bharti3Said M. Afify4Lauren Schnitkey5Daniel T. Wynn6Fan Yang7Thomas M. Rohwetter8Anmada Nayak9Nawat Bunnag10Carolina Cywiak11Hsin-Yao Tang12Brent T. Harris13Christopher Albanese14Chukwuemeka Ihemelandu15Melanie H. Cobb16Arminja Kettenbach17Ethan Lee18Yashi Ahmed19David J. Robbins20Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USADepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USADepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USADepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USADepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USADepartment of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USADepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USADepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USADepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USADepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USADepartment of Molecular and Systems Biology and the Dartmouth Cancer Center, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USADepartment of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USAMolecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USADepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USADepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA; Department of Radiology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USADepartment of Surgical Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USADepartment of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USADepartment of Molecular and Systems Biology and the Dartmouth Cancer Center, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USADepartment of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USADepartment of Molecular and Systems Biology and the Dartmouth Cancer Center, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USADepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA; Corresponding authorSummary: The mechanism by which Wnt signaling, an essential pathway controlling development and disease, stabilizes β-catenin has been a subject of debate over the last four decades. Casein kinase 1α (CK1α) functions as a pivotal negative regulator of this signaling pathway, initiating the events that destabilize β-catenin. However, whether and how CK1α activity is regulated in Wnt-off and Wnt-on states remains poorly understood. We now show that CK1α activity requires its association with the α catalytic subunit of protein phosphatase 2A (PPP2CA) on AXIN, the scaffold protein of the β-catenin destruction complex. Wnt stimulation induces the dissociation of PPP2CA from CK1α, resulting in CK1α autophosphorylation and its consequent inactivation. Moreover, autophosphorylated CK1α is enriched in a subset of colorectal cancers (CRCs) harboring constitutive Wnt activation. Our findings identify a mechanism by which Wnt stimulation inactivates CK1α, filling a critical gap in our understanding of Wnt signaling, with relevance for CRC.http://www.sciencedirect.com/science/article/pii/S2211124725000452CP: CancerCP: Molecular biology |
| spellingShingle | Chen Shen Wenhui Lu Siva B. Merugu Aradhana Bharti Said M. Afify Lauren Schnitkey Daniel T. Wynn Fan Yang Thomas M. Rohwetter Anmada Nayak Nawat Bunnag Carolina Cywiak Hsin-Yao Tang Brent T. Harris Christopher Albanese Chukwuemeka Ihemelandu Melanie H. Cobb Arminja Kettenbach Ethan Lee Yashi Ahmed David J. Robbins Wnt signaling inhibits casein kinase 1α activity by modulating its interaction with protein phosphatase 2A Cell Reports CP: Cancer CP: Molecular biology |
| title | Wnt signaling inhibits casein kinase 1α activity by modulating its interaction with protein phosphatase 2A |
| title_full | Wnt signaling inhibits casein kinase 1α activity by modulating its interaction with protein phosphatase 2A |
| title_fullStr | Wnt signaling inhibits casein kinase 1α activity by modulating its interaction with protein phosphatase 2A |
| title_full_unstemmed | Wnt signaling inhibits casein kinase 1α activity by modulating its interaction with protein phosphatase 2A |
| title_short | Wnt signaling inhibits casein kinase 1α activity by modulating its interaction with protein phosphatase 2A |
| title_sort | wnt signaling inhibits casein kinase 1α activity by modulating its interaction with protein phosphatase 2a |
| topic | CP: Cancer CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725000452 |
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