Phosphorylation of Kindlins and the Control of Integrin Function

Białkowska, Katarzyna; Qin, Jun; Plow, Edward F.

doi:10.3390/cells10040825

Cited by 10 publications

(10 citation statements)

References 80 publications

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“…Phosphorylation is another important aspect of kindlin functionality, which has been validated experimentally at T8 and T30 position for kindlin1; Y193, S159, S181, and S666 for kindlin2; T482 and S484 for kindlin3 29 . Computational predictions indicate a complete loss of T8 and S484 mutation sites in kindlin1 and kindlin3, respectively.…”

Section: Mutations Affects Structure-function Dynamics Of Kindlinsmentioning

confidence: 85%

Pan-cancer Analysis Predicts Kindlin-associated Global Mechanochemical Perturbation

Haldar

Chowdhury

Mistry

et al. 2022

Preprint

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Kindlins are mechanosensitive adapter proteins that connect extracellular mechanical cues to intracellular chemical events. Any alterations in these proteins thus alter cellular signaling, which could result in cancer progression. However, their involvement in global mechanochemical signals remains elusive in cancers. Here we analyze pan-cancer samples to decipher how kindlin alterations aid cancer progression. We show that kindlin alterations, at both the genetic and mRNA level, dysregulates cellular behavior which significantly correlate with poor survival. We find that while these alterations are cancer-specific, they are prevalent in advanced tumor stages and metastatic onset. We observe that kindlins co-alter with a substantial fraction of human mechanochemical proteome in various tumors. Our analysis suggests how kindlin alterations aid tumor-promoting signals with a synergistic effect from alterations of cancer-hallmark genes. Notably, we demonstrate a consistent alteration of epithelial-mesenchymal-transition markers with kindlin activity. Overall, our study highlights how kindlin alterations could affect metabolism, genomic instability, and signal disruption via their interactome network, causing cancer and suggests targeting them as a therapeutic strategy.

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Section: Mutations Affects Structure-function Dynamics Of Kindlinsmentioning

confidence: 85%

Pan-cancer Analysis Predicts Kindlin-associated Global Mechanochemical Perturbation

Haldar

Chowdhury

Mistry

et al. 2022

Preprint

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“…Previous studies have demonstrated that Talin and Kindlin are indispensable mechanosensitive adaptor proteins in integrin activation. − However, details about how Talin and Kindlin synergistically activate integrin were not fully understood. ,, It might be a rational hypothesis that Kindlin assisted Talin in activating integrin via transmitting mechanosignals. We herein studied the effect of tension on the interaction of the β1 integrin cytoplasmic tail with the Talin-F3 domain by performing “ramp-clamp SMD simulations” with different tensile forces.…”

Section: Discussionmentioning

confidence: 99%

Tension Enhances the Binding Affinity of β1 Integrin by Clamping Talin Tightly: An Insight from Steered Molecular Dynamics Simulations

Fang

2022

J. Chem. Inf. Model.

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Integrin activation is a predominant step for cell–cell and cell–ECM interactions. Talin and Kindlin are mechanosensitive adaptor proteins that bind to the integrin cytoplasmic tail and mediate integrin activation, cytoskeleton rearrangement, and focal adhesion assembly. However, knowledge about how Talin and Kindlin synergistically assist integrin activation remains unclear. Here, we performed so-called “ramp-clamp” SMD simulations, which modeled the mechanosignaling from Kindlin, to investigate the effect of tension on the interaction of the β1 integrin cytoplasmic tail with the Talin-F3 domain. The present results showed that mild but not excessive stretching enhanced the binding of integrin with Talin. This mechanical regulation on integrin affinity to Talin referred to an event cascade, in which under stretching, the integrin cytoplasmic tail adopted allostery in response to the mechanical stimulus, remodeling of integrin in favor of Talin-association ensued, and finally, a stable, close-knit complex was formed. In the cascade, the torsion angle transition of integrin was the cue for the stable interaction of the complex under tensile force. The present work suggested a model for Talin and Kindlin to synergistically activate integrin. It should help understand integrin activation and its mechanochemical regulation mechanism, integrin-related innate cellular immune responses, cell adhesion, cell–cell interaction, and integrin-related drug development.

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“…The 14-3-3ζ proteins are dimers and could bind both phosphorylated T/S residues in integrin β-chains and phosphorylated kindlin-3. Kindlin-3 is phosphorylated at several sites, but the double-mutant T482/S484-AA in kindlin-3 inhibited adhesion of T lymphocytes, which shows that phosphorylation of kindlin-3 is functionally important [ 37 , 73 ].…”

Section: The Interactions Of Cytoplasmic Proteins With Integrins Are Regulated By Integrin Phosphorylationmentioning

confidence: 99%

How integrin phosphorylations regulate cell adhesion and signaling

Gahmberg

Grönholm

2022

Trends in Biochemical Sciences

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Cell adhesion is essential for the formation of organs, cellular migration, and interaction with target cells and the extracellular matrix. Integrins are large protein α/β-chain heterodimers and form a major family of cell adhesion molecules. Recent research has dramatically increased our knowledge of how integrin phosphorylations regulate integrin activity. Phosphorylations determine the signaling complexes formed on the cytoplasmic tails, regulating downstream signaling. α-Chain phosphorylation is necessary for inducing β-chain phosphorylation in LFA-1, and the crosstalk from one integrin to another activating or inactivating its function is in part mediated by phosphorylation of β-chains. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus receptor angiotensin-converting enzyme 2 (ACE2) and possible integrin coreceptors may crosstalk and induce a phosphorylation switch and autophagy.

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Phosphorylation of Kindlins and the Control of Integrin Function

Cited by 10 publications

References 80 publications

Pan-cancer Analysis Predicts Kindlin-associated Global Mechanochemical Perturbation

Pan-cancer Analysis Predicts Kindlin-associated Global Mechanochemical Perturbation

Tension Enhances the Binding Affinity of β1 Integrin by Clamping Talin Tightly: An Insight from Steered Molecular Dynamics Simulations

How integrin phosphorylations regulate cell adhesion and signaling

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