2016
DOI: 10.1517/14728222.2016.1135131
|View full text |Cite
|
Sign up to set email alerts
|

Abstract: An oncogenic GTP-bound K-Ras4B/CaM/PI3Kα complex is supported by available experimental and clinical data; therefore, targeting it may address a pressing therapeutic need. High resolution electron microscopy (EM) or crystal structure of the tripartite complex would allow orthosteric or allosteric drug discovery to disrupt the CaM/PI3Kα interface and thus Akt/mTOR signaling. However, since drug resistance is expected to develop, combining it with compensatory pathways, particularly those involved in cell-cycle … Show more

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...
2
1
1
1

Citation Types

2
42
0

Year Published

2016
2016
2020
2020

Publication Types

Select...
8

Relationship

5
3

Authors

Journals

citations
Cited by 29 publications
(44 citation statements)
references
References 133 publications
2
42
0
Order By: Relevance
“…Since RASSF5 binds at the effector binding site, it is not Ras isoform-specific. 4952 Its two domains link Ras and the MAPK (tumor cell proliferation-promoting), and Hippo (tumor cell proliferation-suppressing) pathways, thereby enabling RASSF5’s tumor suppressing action. At the same time, its N-terminal region, including its putative C1 domain, anchor it to the membrane, further stimulating MST1/2 activation.…”
Section: Discussionmentioning
confidence: 99%
“…Since RASSF5 binds at the effector binding site, it is not Ras isoform-specific. 4952 Its two domains link Ras and the MAPK (tumor cell proliferation-promoting), and Hippo (tumor cell proliferation-suppressing) pathways, thereby enabling RASSF5’s tumor suppressing action. At the same time, its N-terminal region, including its putative C1 domain, anchor it to the membrane, further stimulating MST1/2 activation.…”
Section: Discussionmentioning
confidence: 99%
“…K-Ras has two alternative splicing variants: K-Ras4A and the most abundant K-Ras4B. Elucidating CaM’s mode of action will enable developing K-Ras4B–specific medications [5, 12, 1518]. Despite some clues [2, 6, 19, 20], this question has proven immensely challenging.…”
Section: The Puzzle Of Calmodulin’s Critical Action In Kras-driven Camentioning
confidence: 99%
“…One posited that K-Ras binding to CaM reduces the activity of Ca 2+ -dependent protein kinase II (CaMKII) and expression of frizzled-8 precursor (Fzd8) protein. Depletion of Fzd8 in H-Ras G12V -transformed cells stimulates tumor initiation [15]; the thesis of another [5, 12] was that CaM is an integral component of a K-Ras4B/phosphatidylinositide-3-kinase α (PI3Kα) ternary complex, where CaM molecules bind the Src homology 2 (SH2) domains of the p85 subunit of PI3Kα. Both hypotheses raise questions.…”
Section: The Puzzle Of Calmodulin’s Critical Action In Kras-driven Camentioning
confidence: 99%
“…Based on our mechanistic view of how CaM/Ca 2+ acts to promote adenocarcinomas – through full activation of PI3Kα in KRAS -driven cancers – we proposed that it forms a K-Ras4B/CaM/PI3Kα complex. 94,193 We reasoned that under normal physiological signaling, receptor tyrosine kinase (RTK) collaborates with K-Ras in recruiting and activating PI3K at the membrane. In contrast, oncogenic constitutive K-Ras4B signaling proceeds in the absence of a stimulated RTK.…”
Section: K-ras4b/calmodulin/pi3kα Complexes As a Potential New Adenmentioning
confidence: 99%
“…A distinguishing feature of the HVR of K-Ras4B is bearing a polybasic stretch that is highlighted by a red box. Modified with permission from ref 193. Copyright 2016 Informa Healthcare.…”
Section: Figmentioning
confidence: 99%