Mechanisms of integrin activation and trafficking

Margadant, Coert; Monsuur, Hanneke N.; Norman, Jim C.; Sonnenberg, Arnoud

doi:10.1016/j.ceb.2011.08.005

Cited by 264 publications

(270 citation statements)

References 51 publications

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“…Rather, our data are consistent with these fragments altering the ability of the extracellular domain of TrkA to interact with and bind its ligands. We speculate that this is by an inside-out structural modulation similar to that which occurs during activation of the integrin receptor (57).…”

Section: Discussionmentioning

confidence: 92%

An Intracellular Domain Fragment of the p75 Neurotrophin Receptor (p75NTR) Enhances Tropomyosin Receptor Kinase A (TrkA) Receptor Function

Matusica

Skeldal

Sykes

et al. 2013

Journal of Biological Chemistry

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Background:The mechanism by which the p75 neurotrophin receptor (p75 NTR ) and TrkA interact to enhance neurotrophin signaling is unknown. Results: The p75NTR intracellular domain fragment, p75 ICD , but not full-length p75 NTR enhanced NGF binding to TrkA and neurite outgrowth. Conclusion:The results suggest that p75 ICD causes a conformational change within the extracellular domain of TrkA. Significance: The findings challenge our current understanding of how p75 NTR enhances neurotrophic activity.

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Section: Discussionmentioning

confidence: 92%

An Intracellular Domain Fragment of the p75 Neurotrophin Receptor (p75NTR) Enhances Tropomyosin Receptor Kinase A (TrkA) Receptor Function

Matusica

Skeldal

Sykes

et al. 2013

Journal of Biological Chemistry

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“…To our knowledge, these are the first observations that posttranscriptional integrin regulation can be driven by matrix rigidity in fibroblasts. Unraveling the molecular complexity underlying such posttranscriptional regulation (39,40) will require future investigations. However, whatever the regulatory mechanism might be, it is conceivable that the functional role of the enhanced b 1 integrin level is to reinforce the b 1 /FAK pY397 /Akt pS473 mechano-regulatory pathway to further stabilize focal adhesions and fibroblast accumulation as outlined in Fig.…”

Section: Discussionmentioning

confidence: 99%

Matrix Stiffening and β1 Integrin Drive Subtype-Specific Fibroblast Accumulation in Lung Cancer

Puig

Lugo

Gabasa

et al. 2015

Molecular Cancer Research

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The crucial role of tumor-associated fibroblasts (TAF) in cancer progression is now clear in non-small cell lung cancer (NSCLC). However, therapies against TAFs are limited due to a lack of understanding in the subtype-specific mechanisms underlying their accumulation. Here, the mechanical (i.e., matrix rigidity) and soluble mitogenic cues that drive the accumulation of TAFs from major NSCLC subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC) were dissected. Fibroblasts were cultured on substrata engineered to exhibit normal-or tumor-like stiffnesses at different serum concentrations, and critical regulatory processes were elucidated. In control fibroblasts from nonmalignant tissue, matrix stiffening alone increased fibroblast accumulation, and this mechanical effect was dominant or comparable with that of soluble growth factors up to 0.5% serum. The stimulatory cues of matrix rigidity were driven by b1 integrin mechanosensing through FAK (pY397), and were associated with a posttranscriptionally driven rise in b1 integrin expression. The latter mechano-regulatory circuit was also observed in TAFs but in a subtype-specific fashion, because SCC-TAFs exhibited higher FAK (pY397), b1 expression, and ERK1/2 (pT202/Y204) than ADCTAFs. Moreover, matrix stiffening induced a larger TAF accumulation in SCC-TAFs (>50%) compared with ADC-TAFs (10%-20%). In contrast, SCC-TAFs were largely serum desensitized, whereas ADC-TAFs responded to high serum concentration only. These findings provide the first evidence of subtype-specific regulation of NSCLC-TAF accumulation. Furthermore, these data support that therapies aiming to restore normal lung elasticity and/or b1 integrin-dependent mechano regulation may be effective against SCC-TAFs, whereas inhibiting stromal growth factor signaling may be effective against ADC-TAFs.Implications: This study reveals distinct mechanisms underlying the abnormal accumulation of tumor-supporting fibroblasts in two major subtypes of lung cancer, which will assist the development of personalized therapies against these cells.

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“…8D, I). Integrins are known to be recycled through Rab11-, Rab8-and Rab4-dependent pathways (Bridgewater et al, 2012;Margadant et al, 2011;Sharma et al, 2009). To find an explanation why FA turnover and recycling of integrins in shR1 cells are increased (as shown in Fig.…”

Section: Reggie-1 Controls the Number Of Fas Via Rab11amentioning

confidence: 99%

“…Integrin ␣-and ␤-subunits assemble in a cell-type specific manner and serve as receptors for distinct extracellular matrix proteins, soluble ligands and RGD-containing proteins (Margadant et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…During cell migration, integrins and FAs undergo rapid turnover (Margadant et al, 2011), a process that includes recycling and the targeted re-delivery of integrins and integrin-interacting components to newly forming focal contacts and nascent FAs (Caswell et al, 2009). Integrin recycling requires EHD1-(epsin homology domain containing protein 1) positive cargo vesicle trafficking controlled by Rab and Rho-GTPases and the cytoskeleton (Caswell et al, 2009;Grant and Donaldson, 2009;Jovic et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Reggie-1/Flotillin-2 regulates integrin trafficking and focal adhesion turnover via Rab11a

Hülsbusch

Solis

Katanaev

et al. 2015

European Journal of Cell Biology

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a b s t r a c tReggies/flotillins are implicated in trafficking of membrane proteins to their target sites and in the regulation of the Rab11a-dependent targeted recycling of E-cadherin to adherens junctions (AJs). Here we demonstrate a function of reggies in focal adhesion (FA) formation and ␣5-and ␤1-integrin recycling to FAs. Downregulation of reggie-1 in HeLa and A431 cells by siRNA and shRNA increased the number of FAs, impaired their distribution and modified FA turnover. This was coupled to enhanced focal adhesion kinase (FAK) and Rac1 signaling and gain in plasma membrane motility. Wild type and constitutively-active (CA) Rab11a rescued the phenotype (normal number of FAs) whereas dominant-negative (DN) Rab11a mimicked the loss-of-reggie phenotype in control cells. That reggie-1 affects integrin trafficking emerged from the faster loss of internalized antibody-labeled ␤1-integrin in reggie-deficient cells. Moreover, live imaging using TIRF microscopy revealed vesicles containing reggie-1 and ␣5-or ␤1-integrin, trafficking close to the substrate-near membrane and making kiss-and-run contacts with FAs. Thus, reggie-1 in interaction with Rab11a controls Rac1 and FAK activation and coordinates the targeted recycling of ␣5-and ␤1-integrins to FAs to regulate FA formation and membrane dynamics.

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Mechanisms of integrin activation and trafficking

Cited by 264 publications

References 51 publications

An Intracellular Domain Fragment of the p75 Neurotrophin Receptor (p75NTR) Enhances Tropomyosin Receptor Kinase A (TrkA) Receptor Function

An Intracellular Domain Fragment of the p75 Neurotrophin Receptor (p75NTR) Enhances Tropomyosin Receptor Kinase A (TrkA) Receptor Function

Matrix Stiffening and β1 Integrin Drive Subtype-Specific Fibroblast Accumulation in Lung Cancer

Reggie-1/Flotillin-2 regulates integrin trafficking and focal adhesion turnover via Rab11a

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