The Fibrillin-1 RGD Integrin Binding Site Regulates Gene Expression and Cell Function through microRNAs

Zeyer, Karina A.; Zhang, Rong-Mo; Kumra, Heena; Hassan, Amani; Reinhardt, Dieter P.

doi:10.1016/j.jmb.2018.11.021

Cited by 20 publications

(30 citation statements)

References 81 publications

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“…We previously identified miR-1208 as one of the most downregulated miRNAs when fibroblasts grow on fibrillin-1. 28 Here we demonstrate that upon fibroblast interaction with fibrillin-1 RGD, the decreased miR-1208 levels elevated ERK1/2 signaling via posttranscriptionally upregulating the protein levels of ERK1/2 and MEK1/2. This led to increased levels of the phosphorylated forms (pERK1/2 and pMEK1/2), due to increased availability of the substrates (see mechanism II above).…”

Section: Rf1m-wtmentioning

confidence: 64%

“…We showed previously that poly-D-lysine does not affect integrin-triggered signaling. 28 The plates were then washed twice with serum-free DMEM medium, before cell seeding.…”

Section: Cell Culturementioning

confidence: 99%

“…This coating concentration was previously optimized for promoting cell adhesion. 28 For some experiments to facilitate cell adhesion for qPCR after 8 hours of seeding (Figure 1D and Figure S1), additional poly-D-lysine (100 µg/ mL, Cultrex, Gaithersburg, MD, USA, cat#3439-100-01) was coated (2 hours at room temperature) after the recombinant proteins. We showed previously that poly-D-lysine does not affect integrin-triggered signaling.…”

Section: Cell Culturementioning

confidence: 99%

“…Our previous study identified a subset of miRNAs regulated by fibrillin-1 RGD-cell interaction, with miR-1208 being one of the most downregulated miRNAs. 28 The current study explored the detailed role of miR-1208 in fibrillin-1-regulated fibroblast proliferation. Fibrillin-1 RGD suppresses miR-1208 expression through c-Src and JNK signaling, and miR-1208 in turn posttranscriptionally regulates the activation of ERK1/2 signaling by controlling ERK2 and MEK1 levels.…”

Section: Introductionmentioning

confidence: 99%

“…[22][23][24] Integrin binding can elicit ERK1/2 and JNK signaling via activation of focal adhesion kinase (FAK), c-Src kinase, and Fyn kinase (reviewed in 25,26). Fibrillin-1 RGD is reported to activate FAK, 27,28 and FAK in turn can recruit and activate c-Src kinase. 29 Independent of FAK, β3 integrin can also activate c-Src kinase directly.…”

Section: Introductionmentioning

confidence: 99%

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The fibrillin‐1 RGD motif posttranscriptionally regulates ERK1/2 signaling and fibroblast proliferation via miR‐1208

et al. 2021

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Fibrillin-1 is an extracellular matrix protein which contains one conserved RGD integrin-binding motif. It constitutes the backbone of microfibrils in many tissues, and mutations in fibrillin-1 cause various connective tissue disorders. Although it is well established that fibrillin-1 interacts with several RGD-dependent integrins, very little is known about the associated intracellular signaling pathways. Recent published evidence identified a subset of miRNAs regulated by fibrillin-1 RGD-cell adhesion, with miR-1208 among the most downregulated. The present study shows that the downregulated miR-1208 controls fibroblast proliferation. Inhibitor experiments revealed that fibrillin-1 RGD suppressed miR-1208 expression via c-Src kinase and the downstream JNK signaling. Bioinformatic prediction and experimental target sequence validation demonstrated four miR-1208 binding sites on the ERK2 mRNA and one on the MEK1 mRNA. ERK2 and MEK1 are critical proliferationpromoting kinases. Decreased miR-1208 levels elevated the total and phosphorylated ERK1/2 and MEK1/2 protein levels and the phosphorylated to total ERK1/2 ratio.Together, the data demonstrate a novel outside-in signaling mechanism explaining how fibrillin-1 RGD-cell binding regulates fibroblast proliferation.

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Section: Rf1m-wtmentioning

confidence: 64%

“…We showed previously that poly-D-lysine does not affect integrin-triggered signaling. 28 The plates were then washed twice with serum-free DMEM medium, before cell seeding.…”

Section: Cell Culturementioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The fibrillin‐1 RGD motif posttranscriptionally regulates ERK1/2 signaling and fibroblast proliferation via miR‐1208

et al. 2021

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Role of fibrilins in human cancer: A narrative review

Mahdizadehi,

Saghaeian Jazi,

Mir

et al. 2023

Health Science Reports

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Background: Fibrillin is one of the extracellular matrix glycoproteins and participates in forming microfibrils found in many connective tissues. The microfibrils enable the elasticity and stretching properties of the ligaments and support connective tissues.There are three isoforms of fibrillin molecules identified in mammals: fibrillin 1 (FBN1), fibrillin 2 (FBN2), and fibrillin 3.Objective: Multiple studies have shown that mutations in these genes or changes in their expression levels can be related to various diseases, including cancers. In this study, we focus on reviewing the role of the fibrillin family in multiple cancers. Methods and Results:We performed a comprehensive literature review to search PubMed and Google Scholar for studies published so far on fibrillin gene expression and its role in cancers. In this review, we have focused on the expression of FBN1 and FBN2 genes in cancers such as the lung, intestine, ovary, pancreatic ductal, esophagus, and thyroid. Conclusion:Altogether various studies showed higher expression of fibrillins in different tumor tissues correlated with the patient's survival. However, there are controversial findings, as some other cancers showed hypermethylated FBN promoters with lower gene expression levels.

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The fibrillinopathies: New insights with focus on the paradigm of opposing phenotypes for both FBN1 and FBN2

et al. 2022

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Different pathogenic variants in the fibrillin-1 gene (FBN1) cause Marfan syndrome and acromelic dysplasias. Whereas the musculoskeletal features of Marfan syndrome involve tall stature, arachnodactyly, joint hypermobility, and muscle hypoplasia, acromelic dysplasia patients present with short stature, brachydactyly, stiff joints, and hypermuscularity. Similarly, pathogenic variants in the fibrillin-2 gene (FBN2) cause either a Marfanoid congenital contractural arachnodactyly or a FBN2-related acromelic dysplasia that most prominently presents with brachydactyly. The phenotypic and molecular resemblances between both the FBN1 and FBN2-related disorders suggest that reciprocal pathomechanistic lessons can be learned. In this review, we provide an updated overview and comparison of the phenotypic and mutational spectra of both the "tall" and "short" fibrillinopathies. The future parallel functional study of both FBN1/2-related disorders will reveal new insights into how pathogenic fibrillin variants differently affect the fibrillin microfibril network and/or growth factor homeostasis in clinically opposite syndromes. This knowledge may eventually be translated into new therapeutic approaches by targeting or modulating the fibrillin microfibril network and/or the signaling pathways under its control.

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The Fibrillin-1 RGD Integrin Binding Site Regulates Gene Expression and Cell Function through microRNAs

Cited by 20 publications

References 81 publications

The fibrillin‐1 RGD motif posttranscriptionally regulates ERK1/2 signaling and fibroblast proliferation via miR‐1208

The fibrillin‐1 RGD motif posttranscriptionally regulates ERK1/2 signaling and fibroblast proliferation via miR‐1208

Role of fibrilins in human cancer: A narrative review

The fibrillinopathies: New insights with focus on the paradigm of opposing phenotypes for both FBN1 and FBN2

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