ArticleOncogene2010
K-Ras4B phosphorylation at Ser181 is inhibited by calmodulin and modulates K-Ras activity and function.
Article in Oncogene, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 76 citations in OpenAlex.
- Drugging Ras trafficking-are there new roads to travel?npj drug discovery · 2025Review
- ROS production by mitochondria: function or dysfunction?Oncogene · 2024Review
- K-Ras Binds Calmodulin-Related Centrin1 with Potential Implications for K-Ras Driven Cancer Cell Stemness.Cancers · 2023Article
- Review
- Dynamic regulation of RAS and RAS signaling.The Biochemical journal · 2023Article
- α4-α5 Helices on Surface of KRAS Can Accommodate Small Compounds That Increase KRAS Signaling While Inducing CRC Cell Death.International journal of molecular sciences · 2023Article
- The Four Homeostasis Knights: In Balance upon Post-Translational Modifications.International journal of molecular sciences · 2022Review
- Calcium channel blockers potentiate gemcitabine chemotherapy in pancreatic cancer.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Post-translational modification of RAS proteins.Current opinion in structural biology · 2021Review
- Review
- KRAS phosphorylation regulates cell polarization and tumorigenic properties in colorectal cancer.Oncogene · 2021Article
- KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Promotion of cancer cell stemness by Ras.Biochemical Society transactions · 2021Review
- The Ins and Outs of RAS Effector Complexes.Biomolecules · 2021Review
- PHLPPing the balance: restoration of protein kinase C in cancer.The Biochemical journal · 2021Review
- Review
- A Covalent Calmodulin Inhibitor as a Tool to Study Cellular Mechanisms of K-Ras-Driven Stemness.Frontiers in cell and developmental biology · 2021Article
- Influence of Cholesterol on the Orientation of the Farnesylated GTP-Bound KRas-4B Binding with Anionic Model Membranes.Membranes · 2020Article
- Article
- Small GTPase RAS in multiple sclerosis - exploring the role of RAS GTPase in the etiology of multiple sclerosis.Small GTPases · 2020Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Fine tuning of Ras activity is widely known as a mechanism to induce different cellular responses. Recently, we have shown that calmodulin (CaM) binds to K-Ras and that K-Ras phosphorylation inhibits its interaction with CaM. In this study we report that CaM inhibits K-Ras phosphorylation at Ser181 by protein kinase C (PKC) in vivo, and this is a mechanism to modulate K-Ras activity and signaling. Although CaM inhibition increased the activation of endogenous K-Ras, PKC inhibition decreased its activation status. We demonstrate that K-Ras phosphorylation decreased susceptibility to p120GAP activity. Accordingly, we also observed that non-phosphorylable K-Ras mutant exhibits a less sustained activation profile and do not efficiently activate AKT at low growth factor doses compared with wild-type K-Ras. It is interesting that the physiological responses induced by K-Ras are affected by this phosphorylation; when K-Ras cannot be phosphorylated it exhibits a remarkably decreased ability to stimulate proliferation in non-saturated serum conditions. Finally, we demonstrate that phosphorylation also regulates oncogenic K-Ras functions, as focus formation capacity, mobility and apoptosis resistance upon adriamycin treatment of cells expressing oncogenic K-Ras that cannot be phosphorylated are highly compromised. Moreover, at low serum concentration proliferation and survival is practically inhibited when cells cannot phosphorylate oncogenic K-Ras. In this condition, K-Ras phosphorylation is essential to ensure a proper activation of mitogen-activated protein kinase and PI3K/AKT pathways. In summary, our findings suggest that the interplay between CaM interaction and PKC phosphorylation is essential to regulate non-oncogenic and oncogenic K-Ras activity and functionality.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.