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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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			Action	DRS
	20200826_coreQEP2_BaSt_LC12-18_SA_Orbi3625_TP_Sample01.raw	Raw
	20200826_coreQEP2_BaSt_LC12-18_SA_Orbi3625_TP_Sample02.raw	Raw
	20200826_coreQEP2_BaSt_LC12-18_SA_Orbi3625_TP_Sample03.raw	Raw
	20200826_coreQEP2_BaSt_LC12-18_SA_Orbi3625_TP_Sample04.raw	Raw
	20200826_coreQEP2_BaSt_LC12-18_SA_Orbi3625_TP_Sample05.raw	Raw

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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.

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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

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

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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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