Mechanical force can enhance c-Src kinase activity by impairing autoinhibition

Daday, Csaba; Buhr, Svenja de; Mercadante, Davide; Gräter, Frauke

doi:10.1016/j.bpj.2022.01.028

Cited by 7 publications

(4 citation statements)

References 42 publications

(47 reference statements)

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“…Like the Src family kinases [66] , [67] , [68] , Abl contains SH2 and SH3 domains docking onto the kinase domain, which is critical for the autoinhibition [69] . Pioneering simulation works have implied that the SH2-SH3 module is rigid, maintained by the SH2-SH3 connector [43] , [70] .…”

Section: Resultsmentioning

confidence: 99%

Allosteric regulation of autoinhibition and activation of c-Abl

Liu

Zhang²,

Tsai³

et al. 2022

Computational and Structural Biotechnology Journal

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Section: Resultsmentioning

confidence: 99%

Allosteric regulation of autoinhibition and activation of c-Abl

Liu

Zhang²,

Tsai³

et al. 2022

Computational and Structural Biotechnology Journal

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“…Cell-matrix or cell-cell junctions have been proposed to allow ECs to sense mechanical forces (55). In particular, our in vitro assays have shown that ECs have enhanced adhesion capabilities to FN and OPN, possibly through interactions with integrin receptors (24).…”

Section: Discussionmentioning

confidence: 99%

Efficient fine-tuning of endothelial gene expression by a single Tyrosine to Phenylalanine point mutation in theVE-cadheringene

Garnier,

Jeanneret,

Durand

et al. 2024

Preprint

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We aimed at understanding whether the site Y685 of VE-cadherin triggers epigenetic programming in vivo. Using our knock-in mice carrying the Y685F VE-cadherin mutation, RNA sequencing from lung ECs identified 884 differentially expressed genes (DEGs) involved in cell-cell adhesion, vascular development, and angiogenesis. Analysis of the VEGF/VEGFR2 signaling pathway shows a significant decrease in the expression of pY1173VEGFR2 whereas VEGF remains constant, this was consistent with impaired migration, proliferation and protrusive properties of ECs in vitro. Co-immunoprecipitation experiments showed that c-Src and Y685F VE-cadherin association which was enhanced in KI compared to WT, resulting in increased in Y685F-VE-cadherin phosphorylation at site Y731. As a consequence, its partner b-catenin translocates to the nucleus. Using CHIPS assay we demonstrate that FOXF1 binds to the s1pr1 promoter, leading to increased expression of the S1PR1, a process associated with increased vessel wall thickness and reduced fibrosis in the lung vasculature in vivo. Overall, our findings provide a novel transcriptomic profile triggered by Y685F-VE-cadherin ECs for potential insights into therapeutic targets to envisage normalisation of the tumor vasculature.

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“…In fact, N-cap residues 15-60, which have been shown to be irrelevant for Abl inhibition ( Hantschel et al, 2003 ), encompass a number of basic residues (K24, K28, K29, R33) and could interact with acidic membrane lipids found at focal contacts. Src kinase also features basic residues near its myristoylation site which stabilize the interaction with PIP 2 -rich membranes ( Daday et al, 2022 ). We speculate that a membrane also enhances Myr unbinding from Abl and Myr insertion by using these residues as a guide for Myr.…”

Section: Discussionmentioning

confidence: 99%

Myristoyl’s dual role in allosterically regulating and localizing Abl kinase

Buhr

Gräter

2022

Preprint

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c-Abl kinase, a key signalling hub in many biological processes ranging from cell development to proliferation, is tightly regulated by two inhibitory Src homology domains. An N-terminal myristoyl-modification can bind to a hydrophobic pocket in the kinase C-lobe, which stabilizes the auto-inhibitory assembly. Activation is triggered by myristoyl release. We used molecular dynamics simulations to show how both myristoyl and the Src homology domains are required to impose the full inhibitory effect on the kinase domain, and reveal the allosteric transmission pathway at residue-level resolution. Importantly, we find myristoyl insertion into a membrane to thermodynamically compete with binding to c-Abl. Myristoyl thus not only localizes the protein to the cellular membrane, but membrane attachment at the same time enhances activation of c-Abl by stabilizing its pre-activated state. Our data put forward a model in which lipidation tightly couples kinase localization and regulation, a scheme that currently appears to be unique for this non-receptor tyrosine kinase.

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Mechanical force can enhance c-Src kinase activity by impairing autoinhibition

Cited by 7 publications

References 42 publications

Allosteric regulation of autoinhibition and activation of c-Abl

Allosteric regulation of autoinhibition and activation of c-Abl

Efficient fine-tuning of endothelial gene expression by a single Tyrosine to Phenylalanine point mutation in theVE-cadheringene

Myristoyl’s dual role in allosterically regulating and localizing Abl kinase

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