Regulation of Integrin Activity by Phosphorylation

Gahmberg, Carl G.; Grönholm, Mikaela; Uotila, Liisa M.

doi:10.1007/978-94-017-9153-3_6

Cited by 15 publications

(29 citation statements)

References 76 publications

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“…Tyrosine phosphorylation of integrin β1 subunit inhibits talin and kindlin binding to NPXY sequence leaving room for other proteins to bind, for example, filamin and tensin [28]. Loss of talin and kindlin from the CT domain of integrin β3 leads to inactivation of the integrin, which is conducive to recycling of integrin molecules and is important for persistent cell migration.…”

Section: Discussionmentioning

confidence: 99%

Sulfatide interacts with and activates integrin αVβ3 in human hepatocellular carcinoma cells

Wang

Dong

et al. 2016

Oncotarget

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Integrin αVβ3 is a malignant driver of anchorage-independence and tumor angiogenesis, but its dysregulation in hepatocellular carcinoma (HCC) remains unclear. In this study, we observed that sulfatide significantly promoted integrin αV(ITGAV) expression and wound closure in HCC. We also noted that elevated sulfatide profoundly stimulated integrin αVβ3 clustering and signaling. In the cells with integrin αVβ3 clustering induced by sulfatide, integrin β3 subunit was phosphorylated. Simultaneously, focal adhesion kinase (FAK), Src and paxillin were also phosphorylated. Treatment with FAK inhibitor resulted in robust suppression of FAK-Y397 and Src-Y416 phosphorylation stimulated by sulfatide, but not suppression of integrin β3 phosphorylation. Src inhibitors repressed Src-Y416 and FAK Y861 and Y925 phosphorylation, but not FAK-Y397 and integrin β3 phosphorylation. After mutation of integrin β3 (Y773F and Y785F), FAK or Src phosphorylation failed to be stimulated by sulfatide. Moreover, β3 Y773 and Y785 phosphorylation was suppressed by insulin-like growth factor receptor knockdown even in cells stimulated by sulfatide. In assays of immunoprecipitation and immunostaining with integrin αV or β3 antibody, labeled sulfatide was found in the complex and co-localized with integrin αVβ3. Taken together, this study demonstrated that elevated sulfatide bound to integrin αVβ3 and induced clustering and phosphorylation of αVβ3 instead of matrix ligand binding, triggering outside-in signaling.

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Section: Discussionmentioning

confidence: 99%

Sulfatide interacts with and activates integrin αVβ3 in human hepatocellular carcinoma cells

Wang

Dong

et al. 2016

Oncotarget

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“…They may employ signaling transduction pathways also used by chemoreceptors, e.g., mechanosensitive G protein coupled receptors (GPCRs) [2]. Further, mechanoreceptors are subject to chemical modifications that affect their ability to function; for example, integrin activity is modulated by phosphorylation [10]. Finally, mechanosensors may contain peptide sequences that are exposed when mechanical force is applied, thereby becoming accessible to their chemical ligand that then binds and changes their activity or function.…”

Section: Introductionmentioning

confidence: 99%

Coincidence Detection of Membrane Stretch and Extracellular pH by the Proton-Sensing Receptor OGR1 (GPR68)

et al. 2018

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Highlights d OGR1 (aka GPR68) requires cell stretch and extracellular protons to activate d Cell stretch and extracellular acidosis synergistically promote OGR1 signaling d Cell-stretch-mediated actin polymerization is crucial for OGR1 activity d Actin depolymerization limits how long OGR1 stays responsive after cell stretch SUMMARYThe physical environment critically affects cell shape, proliferation, differentiation, and survival by exerting mechanical forces on cells. These forces are sensed and transduced into intracellular signals and responses by cells. A number of different membrane and cytoplasmic proteins have been implicated in sensing mechanical forces, but the picture is far from complete, and the exact transduction pathways remain largely elusive. Furthermore, mechanosensation takes place alongside chemosensation, and cells need to integrate physical and chemical signals to respond appropriately and ensure normal tissue and organ development and function. Here, we report that ovarian cancer G protein coupled receptor 1 (OGR1) (aka GPR68) acts as coincidence detector of membrane stretch and its physiological ligand, extracellular H + . Using fluorescence imaging, substrates of different stiffness, microcontact printing methods, and cell-stretching techniques, we show that OGR1 only responds to extracellular acidification under conditions of membrane stretch and vice versa. The level of OGR1 activity mirrors the extent of membrane stretch and degree of extracellular acidification. Furthermore, actin polymerization in response to membrane stretch is critical for OGR1 activity, and its depolymerization limits how long OGR1 remains responsive following a stretch event, thus providing a ''memory'' for past stretch. Cells experience changes in membrane stretch and extracellular pH throughout their lifetime. Because OGR1 is a widely expressed receptor, it represents a unique yet widespread mechanism that enables cells to respond dynamically to mechanical and pH changes in their microenvironment by integrating these chemical and physical stimuli at the receptor level. Current Biology 28, 3815-3823, December 3, 2018 ª 2018 Elsevier Ltd. 3815 FIJI NIH https://fiji.sc/ Driver software for custom built stretch machine Zaber Console https://www.zaber.com/zaber-software e1 Current Biology 28, 3815-3823.e1-e4, December 3, 2018

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“…PKCenzymesthenbecomeactivatedinbothpathwaysandphosphorylate Thr-758 on ␤2. Phosphorylation of the ␤2-chain is known to regulate the affinity for different binding proteins (7). Filamin binds primarily to the unphosphorylated ␤2-chain, whereas ␤2 phosphorylated on Thr-758 binds 14-3-3 proteins and initiates intracellular signaling through Tiam1-Rac1 and inhibitory signaling to ␣4␤1 (12,17,29,30).…”

Section: Discussionmentioning

confidence: 99%

“…COS7 cells were cultured in Dulbecco's modified Eagle's medium and the human T-cell lymphoma cell line J␤2.7, which lacks the ␣L-chain (53), was grown in RPMI 1640 supplemented with 10% FBS, 2 mM L-glutamine, and 100 units/ml penicillin/streptomycin. J␤2.7 cells expressing WT ␣L or S1140A ␣L together with ␤2 have been described (7). K562 cells stably expressing WT ␣X or ␣X S1158A together with ␤2 have been previously described (22).…”

Section: Cell Cultures Immunoprecipitation and Immunoblottingmentioning

confidence: 99%

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Phosphorylation of the α-chain in the integrin LFA-1 enables β2-chain phosphorylation and α-actinin binding required for cell adhesion

Jahan

Madhavan

Rõlova

et al. 2018

Journal of Biological Chemistry

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The integrin leukocyte function-associated antigen-1 (LFA-1) plays a pivotal role in leukocyte adhesion and migration, but the mechanism(s) by which this integrin is regulated has remained incompletely understood. LFA-1 integrin activity requires phosphorylation of its β2-chain and interactions of its cytoplasmic tail with various cellular proteins. The α-chain is constitutively phosphorylated and necessary for cellular adhesion, but how the α-chain regulates adhesion has remained enigmatic. We now show that substitution of the α-chain phosphorylation site (S1140A) in T cells inhibits the phosphorylation of the functionally important Thr-758 in the β2-chain, binding of α-actinin and 14-3-3 protein, and expression of an integrin-activating epitope after treatment with the stromal cell-derived factor-1α. The presence of this substitution resulted in a loss of cell adhesion and directional cell migration. Moreover, LFA-1 activation through the T-cell receptor in cells expressing the S1140A LFA-1 variant resulted in less Thr-758 phosphorylation, α-actinin and talin binding, and cell adhesion. The finding that the LFA-1 α-chain regulates adhesion through the β-chain via specific phosphorylation at Ser-1140 in the α-chain has not been previously reported and emphasizes that both chains are involved in the regulation of LFA-1 integrin activity.

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Regulation of Integrin Activity by Phosphorylation

Cited by 15 publications

References 76 publications

Sulfatide interacts with and activates integrin αVβ3 in human hepatocellular carcinoma cells

Sulfatide interacts with and activates integrin αVβ3 in human hepatocellular carcinoma cells

Coincidence Detection of Membrane Stretch and Extracellular pH by the Proton-Sensing Receptor OGR1 (GPR68)

Phosphorylation of the α-chain in the integrin LFA-1 enables β2-chain phosphorylation and α-actinin binding required for cell adhesion

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