The GSK3 kinase and LZTR1 protein regulate the stability of Ras family proteins and the proliferation of pancreatic cancer cells
Ras family proteins are membrane-bound GTPases that control proliferation, survival, and motility. Many forms of cancers are driven by the acquisition of somatic mutations in a RAS gene. In pancreatic cancer (PC), more than 90% of tumors carry an activating mutation in KRAS. Mutations in components...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-03-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558622000021 |
| _version_ | 1818295928399855616 |
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| author | Chitra Palanivel Neha Chaudhary Parthasarathy Seshacharyulu Jesse L. Cox Ying Yan Surinder K. Batra Michel M. Ouellette |
| author_facet | Chitra Palanivel Neha Chaudhary Parthasarathy Seshacharyulu Jesse L. Cox Ying Yan Surinder K. Batra Michel M. Ouellette |
| author_sort | Chitra Palanivel |
| collection | DOAJ |
| description | Ras family proteins are membrane-bound GTPases that control proliferation, survival, and motility. Many forms of cancers are driven by the acquisition of somatic mutations in a RAS gene. In pancreatic cancer (PC), more than 90% of tumors carry an activating mutation in KRAS. Mutations in components of the Ras signaling pathway can also be the cause of RASopathies, a group of developmental disorders. In a subset of RASopathies, the causal mutations are in the LZTR1 protein, a substrate adaptor for E3 ubiquitin ligases that promote the degradation of Ras proteins. Here, we show that the function of LZTR1 is regulated by the glycogen synthase kinase 3 (GSK3). In PC cells, inhibiting or silencing GSK3 led to a decline in the level of Ras proteins, including both wild type Ras proteins and the oncogenic Kras protein. This decline was accompanied by a 3-fold decrease in the half-life of Ras proteins and was blocked by the inhibition of the proteasome or the knockdown of LZTR1. Irrespective of the mutational status of KRAS, the decline in Ras proteins was observed and accompanied by a loss of cell proliferation. This loss of proliferation was blocked by the knockdown of LZTR1 and could be recapitulated by the silencing of either KRAS or GSK3. These results reveal a novel GSK3-regulated LZTR1-dependent mechanism that controls the stability of Ras proteins and proliferation of PC cells. The significance of this novel pathway to Ras signaling and its contribution to the therapeutic properties of GSK3 inhibitors are both discussed. |
| first_indexed | 2024-12-13T03:55:26Z |
| format | Article |
| id | doaj.art-fecd7e5ec4184873b2e9116838a95734 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 |
| language | English |
| last_indexed | 2024-12-13T03:55:26Z |
| publishDate | 2022-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-fecd7e5ec4184873b2e9116838a957342022-12-22T00:00:38ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862022-03-01252840The GSK3 kinase and LZTR1 protein regulate the stability of Ras family proteins and the proliferation of pancreatic cancer cellsChitra Palanivel0Neha Chaudhary1Parthasarathy Seshacharyulu2Jesse L. Cox3Ying Yan4Surinder K. Batra5Michel M. Ouellette6Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE 68198, USA.Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Corresponding author at: Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA.Ras family proteins are membrane-bound GTPases that control proliferation, survival, and motility. Many forms of cancers are driven by the acquisition of somatic mutations in a RAS gene. In pancreatic cancer (PC), more than 90% of tumors carry an activating mutation in KRAS. Mutations in components of the Ras signaling pathway can also be the cause of RASopathies, a group of developmental disorders. In a subset of RASopathies, the causal mutations are in the LZTR1 protein, a substrate adaptor for E3 ubiquitin ligases that promote the degradation of Ras proteins. Here, we show that the function of LZTR1 is regulated by the glycogen synthase kinase 3 (GSK3). In PC cells, inhibiting or silencing GSK3 led to a decline in the level of Ras proteins, including both wild type Ras proteins and the oncogenic Kras protein. This decline was accompanied by a 3-fold decrease in the half-life of Ras proteins and was blocked by the inhibition of the proteasome or the knockdown of LZTR1. Irrespective of the mutational status of KRAS, the decline in Ras proteins was observed and accompanied by a loss of cell proliferation. This loss of proliferation was blocked by the knockdown of LZTR1 and could be recapitulated by the silencing of either KRAS or GSK3. These results reveal a novel GSK3-regulated LZTR1-dependent mechanism that controls the stability of Ras proteins and proliferation of PC cells. The significance of this novel pathway to Ras signaling and its contribution to the therapeutic properties of GSK3 inhibitors are both discussed.http://www.sciencedirect.com/science/article/pii/S1476558622000021Pancreatic cancerRASLZTR1GSK3Protein stability |
| spellingShingle | Chitra Palanivel Neha Chaudhary Parthasarathy Seshacharyulu Jesse L. Cox Ying Yan Surinder K. Batra Michel M. Ouellette The GSK3 kinase and LZTR1 protein regulate the stability of Ras family proteins and the proliferation of pancreatic cancer cells Neoplasia: An International Journal for Oncology Research Pancreatic cancer RAS LZTR1 GSK3 Protein stability |
| title | The GSK3 kinase and LZTR1 protein regulate the stability of Ras family proteins and the proliferation of pancreatic cancer cells |
| title_full | The GSK3 kinase and LZTR1 protein regulate the stability of Ras family proteins and the proliferation of pancreatic cancer cells |
| title_fullStr | The GSK3 kinase and LZTR1 protein regulate the stability of Ras family proteins and the proliferation of pancreatic cancer cells |
| title_full_unstemmed | The GSK3 kinase and LZTR1 protein regulate the stability of Ras family proteins and the proliferation of pancreatic cancer cells |
| title_short | The GSK3 kinase and LZTR1 protein regulate the stability of Ras family proteins and the proliferation of pancreatic cancer cells |
| title_sort | gsk3 kinase and lztr1 protein regulate the stability of ras family proteins and the proliferation of pancreatic cancer cells |
| topic | Pancreatic cancer RAS LZTR1 GSK3 Protein stability |
| url | http://www.sciencedirect.com/science/article/pii/S1476558622000021 |
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