Calmodulin and PI3K Signaling in KRAS Cancers

Nussinov, Ruth; Wang, Guanqiao; Tsai, Chung Jung; Jang, Hyunbum; Lu, Shaoyong; Banerjee, Avik; Zhang, Jian; Gaponenko, Vadim

doi:10.1016/j.trecan.2017.01.007

Cited by 61 publications

(59 citation statements)

References 88 publications

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“…In this work, we selected KRas4B to explore the structural basis for PI3Ka activation by Ras, because of its frequent expression and thus significance in over-activating PI3Ks in cancer. [49][50][51][52][53] The isoform-specific residues in Ras are all far away from the KRas4B-RBD interface, raising the possibility that these residues may have allosteric effects, albeit likely insignificant, since most of these isoform-specific residues are exposed on the Ras surface. 54 Thus, the structure solved in this work is expected to represent a general Ras-PI3Ka interaction scenario.…”

Section: Discussionmentioning

confidence: 99%

The structural basis for Ras activation of PI3Kα lipid kinase

Zhang

Jang

Nussinov

2019

Phys. Chem. Chem. Phys.

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PI3Ka is a principal Ras effector that phosphorylates PIP 2 to PIP 3 in the PI3K/Akt/mTOR pathway. How Ras activates PI3K has been unclear: is Ras' role confined to PI3K recruitment to the membrane or does Ras activation also involve allostery? Recently, we determined the mechanism of PI3Ka activation at the atomic level. We showed the vital role and significance of conformational change in PI3Ka activation.Here, by a 'best-match for hydrogen-bonding pair' (BMHP) computational protocol and molecular dynamics (MD) simulations, we model the atomic structure of KRas4B in complex with the Ras binding domain (RBD) of PI3Ka, striving to understand the mechanism of PI3Ka activation by Ras. Point mutations T208D, K210E, and K227E disrupt the KRas4B-RBD interface in the models, in line with the experiments. We identify allosteric signaling pathways connecting Ras to RBD in the p110a subunit.However, the observed weak allosteric signals coupled with the detailed mechanism of PI3Ka activation make us conclude that the dominant mechanistic role of Ras is likely to be recruitment and restriction of the PI3Ka population at the membrane. Thus, RTK recruits the PI3Ka to the membrane and activates it by relieving its autoinhibition exerted by the nSH2 domain, leading to exposure of the kinase domain, which permits PIP 2 binding. Ras recruitment can shift the PI3Ka ensemble toward a population where the kinase domain surface and the active site position and orientation favor PIP 2 insertion. This work helps elucidate Ras-mediated PI3K activation and explores the structural basis for Ras-PI3Ka drug discovery.

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Section: Discussionmentioning

confidence: 99%

The structural basis for Ras activation of PI3Kα lipid kinase

Zhang

Jang

Nussinov

2019

Phys. Chem. Chem. Phys.

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“…Protein K -RAS mainly expressed in the cell membrane, and thus played an important role in the development process of tumor [18]. Protein K -RAS had been confirmed of abnormal expression in human malignant tumor, especially in digestive system tumors, such as colorectal cancer [19], gastric cancer [20] and liver cancer [21].…”

Section: Discussionmentioning

confidence: 99%

MiR203 Lost Suppressor Genes Function in the Process of Barrett’s Esophagus Carcinogenesis Because of High Methylation in Promoter

Li¹

2019

CMR

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This study was designed to explore the role of MiR203 promoter methylation in the process of Barrett's esophagus carcinogenesis. RT-PCR was used to detect the expression levels of miRNA-203 in Barrett's esophagus, esophageal cancer and normal esophageal mucosa cell lines, before and after the treatment of demethylation. MiR203 promoter methylation levels in these cell lines were measured by Methylation Specific PCR (MSP). Immunohistochemistry was used to test the expression and distribution of K-Ras, a target of miR203, in esophageal cancer, BE and normal esophagus tissues. The following results were found based on the above methods. MiR203 expression levels were reduced obviously in Barrett esophagus and esophageal cancer cells than normal esophageal cells, the difference was statistically significant (P=0.003). After demethylation treatment, miR203 expression levels were significantly increased in Barrett's esophagus and esophageal cancer cells, the differences were statistically significant (P=0.03). MSP results showed that miR203 promoter changed to be low-methylation or non-methylation after demethylation treatment. In conclusion, MiR203 in Barrett's esophagus and esophageal cancer cells reduced expression is related to its Promoter methylation, miR203 promoter methylation throughout the carcinogenesis of Barrett's esophagus, it may become a key molecular biomarker in process of Barrett esophagus cancerous, and may become the prevention and treatment targets of Barrett esophagus carcinogenesis.

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“…CBP501 did not inhibit Akt/CaM interaction ( Supplementary Figure 7B ). Furthermore, CaM is an integral component of a K-Ras4B/PI3Kɑ ternary complex [ 49 ]. CBP501 may interfere with the trimer formation.…”

Section: Discussionmentioning

confidence: 99%

CBP501 inhibits EGF-dependent cell migration, invasion and epithelial-to-mesenchymal transition of non-small cell lung cancer cells by blocking KRas to calmodulin binding

Saito¹,

Mine²,

Küfe

et al. 2017

Oncotarget

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The anti-cancer agent CBP501 binds to calmodulin (CaM). Recent studies showed that migration and metastasis are inhibited by several CaM antagonists. However, there is no available evidence that CBP501 has similar effects. Here we found that CBP501 inhibits migration of non-small cell lung cancer (NSCLC) cells in vitro, even in the presence of migration inducing factors such as WNT, IL-6, and several growth factors. CBP501 also inhibited epidermal growth factor (EGF) enhanced invasion and the epithelial-to-mesenchymal transition (EMT), and this inhibition was accompanied by (i) suppression of Akt and ERK1/2 phosphorylation, and (ii) suppression of expression of transcription factor Zeb1 and the mesenchymal marker Vimentin. A pull down analysis performed using sepharose-immobilized CaM showed that CBP501 blocks the interaction between CaM and KRas. Furthermore, EGF induced Akt activation and cell migration was effectively suppressed by KRas down-regulation in NSCLC cells. Stable knockdown of KRas also made cells insensitive to CBP501’s inhibition of growth factor-induced migration. Taken together, these results indicate that CBP501 inhibits binding of CaM with KRas and thereby suppresses the PI3K/AKT pathway, migration, invasion and EMT. These findings have identified a previously unrecognized effect of CBP501 on downstream KRas signaling mechanisms involving EMT and invasion, and provide support for the further clinical development of this agent.

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Calmodulin and PI3K Signaling in KRAS Cancers

Cited by 61 publications

References 88 publications

The structural basis for Ras activation of PI3Kα lipid kinase

The structural basis for Ras activation of PI3Kα lipid kinase

MiR203 Lost Suppressor Genes Function in the Process of Barrett’s Esophagus Carcinogenesis Because of High Methylation in Promoter

CBP501 inhibits EGF-dependent cell migration, invasion and epithelial-to-mesenchymal transition of non-small cell lung cancer cells by blocking KRas to calmodulin binding

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