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Lfc phospho-proteome (Lfc subcellular localization and activity is controlled by αv-class integrin)

ABSTRACT: Fibronectin (FN)-binding integrins control a variety of cellular responses through Rho GTPases. The FN-binding integrins, αvβ3 and α5β1, are known to induce different effects on cell morphology and motility. Here we report that FN-bound αvβ3 integrin, but not FN-bound α5β1 integrin, triggers the dissociation of the RhoA GEF Lfc (GEF-H1 in humans) from microtubules (MT), leading to the activation of RhoA, formation of stress fibres and maturation of focal adhesions (FAs). Conversely, loss of Lfc expression decreases RhoA activity, stress fibre formation and FA size, suggesting that Lfc is the major GEF downstream of FN-bound αvβ3 that controls RhoA activity. Mechanistically, FN-engaged αvβ3 integrin activates a kinase cascade involving MARK2/3, which in turn leads to phosphorylation of several phospho-sites on Lfc. In particular, S151 was identified as the main site involved in the regulation of Lfc localization and activity. Our findings indicate that activation of Lfc/RhoA is orchestrated in FN-adherent cells in an integrin-specific manner

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Fibroblast

SUBMITTER: GEORGINA COLO

LAB HEAD: Georgina Pamela Coló

PROVIDER: PXD037633 | Pride | 2023-04-17

REPOSITORIES: Pride

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RhoA GEFs (Lfc subcellular localization and activity is controlled by αv-class integrin)

Project description:Fibronectin (FN)-binding integrins control a variety of cellular responses through Rho GTPases. The FN-binding integrins, αvβ3 and α5β1, are known to induce different effects on cell morphology and motility. Here we report that FN-bound αvβ3 integrin, but not FN-bound α5β1 integrin, triggers the dissociation of the RhoA GEF Lfc (GEF-H1 in humans) from microtubules (MT), leading to the activation of RhoA, formation of stress fibres and maturation of focal adhesions (FAs). Conversely, loss of Lfc expression decreases RhoA activity, stress fibre formation and FA size, suggesting that Lfc is the major GEF downstream of FN-bound αvβ3 that controls RhoA activity. Mechanistically, FN-engaged αvβ3 integrin activates a kinase cascade involving MARK2/3, which in turn leads to phosphorylation of several phospho-sites on Lfc. In particular, S151 was identified as the main site involved in the regulation of Lfc localization and activity. Our findings indicate that activation of Lfc/RhoA is orchestrated in FN-adherent cells in an integrin-specific manner.

2023-04-17 | PXD037596 | Pride

Integrin αvβ3 acting as membrane receptor for thyroid hormones mediates angiogenesis in malignant T cells

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Integrin αvβ3 acting as membrane receptor for thyroid hormones mediates angiogenesis in malignant T cells

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Tumor exosome integrins determine organotropic metastasis

Project description:Stephen Paget first proposed, in 1889, that organ distribution of metastases is a non-random event, yet metastatic organotropism remains one of the greatest mysteries in cancer biology. Here, we demonstrate that exosomes released by lung-, liver- and brain-tropic tumor cells fuse preferentially with resident cells at their predicted destination, such as fibroblasts and epithelial cells in the lung, Kupffer cells in the liver, and endothelial cells in the brain. We found that exosome homing to organ-specific cell types prepares the pre-metastatic niche and that treatment with exosomes derived from lung tropic models can redirect metastasis to the lung. Proteomic profiling of exosomes revealed distinct integrin expression patterns associated with each organ-specific metastasis. Whereas exosomal integrins α6β4 and α6β1 were associated with lung metastasis, exosomal integrins αvβ5 and αvβ3 were linked with liver and brain metastases, respectively. Targeting α6β4 and αvβ5 integrins decreased exosome uptake and metastasis in the lung and liver, respectively. Importantly, we demonstrate that exosome uptake activates a cell-specific subset of S100 family genes, known to support cell migration and niche formation. Finally, our clinical data indicate that integrin-expression profiles in circulating plasma exosomes from cancer patients could be used to predict organ-specific metastasis. Education of human von Kupffer cells in vitro with human pancreatic cancer exosomes

2015-06-17 | E-GEOD-68919 | biostudies-arrayexpress

Tumor exosome integrins determine organotropic metastasis

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The tongue squamous carcinoma cell line Cal27 primarily employs integrin α6β4-containing type II hemidesmosomes for adhesion which contribute to anticancer drug sensitivity

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Project description:Hepatocyte growth factor (HGF) signaling through its receptor Met has been implicated in hepatocellular carcinoma tumorigenesis and progression. Met interaction with integrins is shown to modulate the downstream signaling to Akt and ERK (extracellular-regulated kinase). In this study, we developed a mechanistically detailed systems biology model of HGF/Met signaling pathway that incorporated specific interactions with integrins to investigate the efficacy of integrin-binding peptide, AXT050, as monotherapy and in combination with other therapeutics targeting this pathway. Here we report that the modeled dynamics of the response to AXT050 revealed that receptor trafficking is sufficient to explain the effect of Met-integrin interactions on HGF signaling. Furthermore, the model predicted patient-specific synergy and antagonism of efficacy and potency for combination of AXT050 with sorafenib, cabozantinib, and rilotumumab. Overall, the model provides a valuable framework for studying the efficacy of drugs targeting receptor tyrosine kinase interaction with integrins, and identification of synergistic drug combinations for the patients. Model is encoded by Johannes and submitted to BioModels by Ahmad Zyoud.

2020-03-20 | MODEL2003200001 | BioModels

Potential interactors of alpha-tubulin acetyltransferase 1 (αTAT1/MEC17)

Project description:Cell adhesion to the extracellular matrix occurs through integrin-mediated focal adhesions, which sense the mechanical properties of the substrate and impact cellular functions such as cell migration. Mechanotransduction at focal adhesions affects the actomyosin network and contributes to cell migration. Despite being key players in cell adhesion and migration, the role of microtubules in mechanotransduction has been overlooked. Here, we show that substrate rigidity increases microtubule acetylation through β1 integrin signalling in primary rat astrocytes. Moreover, αTAT1, the enzyme responsible for microtubule acetylation, interacts with a major mechanosensing focal adhesion protein, Talin, and is able to tune the distribution of focal adhesions depending on the matrix rigidity. αTAT1 also reorganises the actomyosin network, increases traction force generation and cell migration speed on stiff substrates. Mechanistically, acetylation of microtubules promotes the release of microtubule-associated RhoGEF, GEF-H1 into the cytoplasm, which then leads to RhoA activation and high actomyosin contractility. Thus, we propose a novel feedback loop involving a crosstalk between microtubules and actin in mechanotransduction at focal adhesions whereby, cells sense the rigidity of the substrate through integrin-mediated adhesions, modulate their levels of microtubule acetylation, which then controls the actomyosin cytoskeleton and force transmission on the substrate to promote mechanosensitive cell migration.

2021-11-02 | PXD015871 | Pride

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Project description:Hypoxia regulates epithelial to mesenchymal transition (EMT) of cancer cells. However, the mechanism underlying hypoxia-mediated EMT remains largely unknow. Here, utilizing colorectal cell carcinoma (CRC) as a model, we find that HUNK inhibits EMT and suppresses metastasis of CRC cells via its substrate GEF-H1 in a kinase-dependent manner. Mechanistically, HUNK directly phosphorylates GEF-H1 at ser645 site, which activates RhoA and consequently leads to a cascade of phosphorylation of LIMK1/CFL-1, thereby stabilizing F-actin and inhibiting EMT. Moreover, hypoxia suppresses HUNK activity and dephosphorylates GEF-H1 to promote EMT. Clinically, the expression levels of both HUNK and phosphorylation of GEH-H1 ser645 are not only downregulated in CRC tissues with metastasis compared to that without metastasis, but also positively correlated among these tissues. Our findings highlight the importance of hypoxia-regulated HUNK kinase activity and phosphorylation of GEF-H1 in regulation of EMT and metastasis of CRC.

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