Collagen remodeling by phagocytosis is determined by collagen substrate topology and calcium-dependent interactions of gelsolin with nonmuscle myosin IIA in cell adhesions

Arora, Pooja; Wang, Y.; Bresnick, Anne R.; Dawson, John F.; Janmey, Paul A.; McCulloch, Christopher A.

doi:10.1091/mbc.e12-10-0754

Cited by 25 publications

(25 citation statements)

References 60 publications

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“…The M C receptor that mediates collagen I binding in fibroblasts and delineated the molecular pathway responsible for collagen phagocytosis in this system ( figure 2A). B I the activation of stretch-activated calcium channels [5], leading to an increase in intracellular calcium concentration [Ca ++ ] i . This mediates the accumulation of the actin-binding protein gelsolin and the non-muscular myosin II A (NMMIIA) at the adhesion sites [5].…”

Section: Integrin Mediates Collagen Phagocytosismentioning

confidence: 99%

“…B I the activation of stretch-activated calcium channels [5], leading to an increase in intracellular calcium concentration [Ca ++ ] i . This mediates the accumulation of the actin-binding protein gelsolin and the non-muscular myosin II A (NMMIIA) at the adhesion sites [5]. Gelsolin-dependent nucleation of actin filaments is required for phagosome formation and the internalisation of collagen to early endosomes [6].…”

Section: Integrin Mediates Collagen Phagocytosismentioning

confidence: 99%

“…Recent pieces of evidence suggest that collagen phagocytosis is strongly dependent on collagen morphology [5], raising the intriguing hypothesis that the complex 3D organisation of the ECM might control its ability to be internalised.…”

Section: Integrin Mediates Collagen Phagocytosismentioning

confidence: 99%

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Extracellular matrix endocytosis in controlling matrix turnover and beyond: emerging roles in cancer

Rainero

2016

Biochemical Society Transactions

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The extracellular matrix (ECM) is a network of secreted proteins that, beyond providing support for tissues and organs, is involved in the regulation of a variety of cell functions, including cell proliferation, polarity, migration and oncogenic transformation. ECM homeostasis is maintained through a tightly controlled balance between synthesis, deposition and degradation. While the role of metalloproteases (MMPs) in ECM degradation is widely recognised, the contribution of ECM internalisation and intracellular degradation to ECM maintenance has been mostly overlooked. In this review, I will summarise what is known about the molecular mechanisms mediating ECM endocytosis and how this process impacts on diseases, such as fibrosis and cancer.

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Section: Integrin Mediates Collagen Phagocytosismentioning

confidence: 99%

Section: Integrin Mediates Collagen Phagocytosismentioning

confidence: 99%

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Extracellular matrix endocytosis in controlling matrix turnover and beyond: emerging roles in cancer

Rainero

2016

Biochemical Society Transactions

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“…In liver, HSCs are important not only for collagen production that contributes to liver cirrhosis, but also for collagen degradation during cirrhosis resolution. Collagen has been reported to be internalized by macrophages and fibroblasts (1,30) and recently by HSCs (36,37). However, the mechanisms and relevance of this process remain undefined and were the focus of this investigation.…”

mentioning

confidence: 99%

Endocytosis of collagen by hepatic stellate cells regulates extracellular matrix dynamics

Bi¹,

Mukhopadhyay²,

Drinane³

et al. 2014

American Journal of Physiology-Cell Physiology

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Hepatic stellate cells (HSCs) generate matrix, which in turn may also regulate HSCs function during liver fibrosis. We hypothesized that HSCs may endocytose matrix proteins to sense and respond to changes in microenvironment. Primary human HSCs, LX2, or mouse embryonic fibroblasts (MEFs) [wild-type; c-abl−/−; or Yes, Src, and Fyn knockout mice (YSF−/−)] were incubated with fluorescent-labeled collagen or gelatin. Fluorescence-activated cell sorting analysis and confocal microscopy were used for measuring cellular internalization of matrix proteins. Targeted PCR array and quantitative real-time PCR were used to evaluate gene expression changes. HSCs and LX2 cells endocytose collagens in a concentration- and time-dependent manner. Endocytosed collagen colocalized with Dextran 10K, a marker of macropinocytosis, and 5-ethylisopropyl amiloride, an inhibitor of macropinocytosis, reduced collagen internalization by 46%. Cytochalasin D and ML7 blocked collagen internalization by 47% and 45%, respectively, indicating that actin and myosin are critical for collagen endocytosis. Wortmannin and AKT inhibitor blocked collagen internalization by 70% and 89%, respectively, indicating that matrix macropinocytosis requires phosphoinositide-3-kinase (PI3K)/AKT signaling. Overexpression of dominant-negative dynamin-2 K44A blocked matrix internalization by 77%, indicating a role for dynamin-2 in matrix macropinocytosis. Whereas c-abl−/− MEF showed impaired matrix endocytosis, YSF−/− MEF surprisingly showed increased matrix endocytosis. It was also associated with complex gene regulations that related with matrix dynamics, including increased matrix metalloproteinase 9 (MMP-9) mRNA levels and zymographic activity. HSCs endocytose matrix proteins through macropinocytosis that requires a signaling network composed of PI3K/AKT, dynamin-2, and c-abl. Interaction with extracellular matrix regulates matrix dynamics through modulating multiple gene expressions including MMP-9.

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“…Fibroblasts mediate receptor-dependent collagen internalization largely through the α2β1 integrin (Lee et al 1996). Subsequently, the mechanism was further examined and was found to involve interaction of the small GTPase Rap1 with non-muscle myosin IIA (Arora, et al 2000(Arora, et al , 2008(Arora, et al , 2013Lee et al 1996).…”

Section: Intracellular Collagen Degradationmentioning

confidence: 99%

Contribution of collagen adhesion receptors to tissue fibrosis

Coelho

McCulloch

2016

Cell Tissue Res

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Fibrosis is the result of a wound-healing response that fails to restore normal tissue structure function. One of the critical hallmarks of fibrosis is disrupted collagen remodeling. In tissue homeostasis, the production, deposition and organization of collagen is balanced by the degradation and remodeling of collagen within the existing matrix. After injury or chronic infection, tissues initiate a wound-healing response that is intended to create a new ECM for restoring tissue structure and function. If the wound-healing response is dysregulated or if the tissue injury or infection is severe or long-lasting, collagen deposition exceeds collagen degradation and the tissue repair process leads to fibrosis. The fibrotic repair response is extraordinarily complex and involves a wide spectrum of cells, signaling pathways and regulatory systems, some of which can be readily disrupted and thereby contribute to fibrotic lesions. The dysregulated collagen remodeling is a common end-point of all fibrotic disorders, and one of the rate-limiting steps of collagen remodeling is the binding of cells to collagen fibrils by specific cell adhesion receptors. In this review, we describe how the expression and function of collagen adhesion receptors contribute to collagen processing events that contribute to tissue fibrosis. Graphical abstract Balance between collagen remodeling in health and disease.

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Collagen remodeling by phagocytosis is determined by collagen substrate topology and calcium-dependent interactions of gelsolin with nonmuscle myosin IIA in cell adhesions

Abstract: Cell adhesion to collagen presented on beads activates Ca2+ entry and promotes the formation of phagosomes enriched with NMMIIA and gelsolin. The Ca2+-dependent interaction of gelsolin and NMMIIA in turn enables actin remodeling and enhances collagen degradation by phagocytosis.

Cited by 25 publications

References 60 publications

Extracellular matrix endocytosis in controlling matrix turnover and beyond: emerging roles in cancer

Extracellular matrix endocytosis in controlling matrix turnover and beyond: emerging roles in cancer

Endocytosis of collagen by hepatic stellate cells regulates extracellular matrix dynamics

Contribution of collagen adhesion receptors to tissue fibrosis

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