The collagen receptor DDR1 regulates cell spreading and motility by associating with myosin IIA

Huang, Yun; Arora, Pooja; McCulloch, Christopher A.; Vogel, Wolfgang F.

doi:10.1242/jcs.046219

Cited by 85 publications

(90 citation statements)

References 42 publications

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“…We also examined the other main MAPKs signaling pathways (JNK, p38, and AKT) and found no significant activation under the applied experimental set-up. Furthermore, we show an increase in collagen receptor Ddr1, which regulates cellular functions such as cell spreading and polarity, in response to ECM-microenvironment alterations (53,54). Overall, the remodeling events of collagenrich ECM by either MMP-1 or MMP-13 contributed to fibroblastmatrix communication, suggesting that such stimulation may be involved in cell migration in normal and pathological processes.…”

Section: Discussionmentioning

confidence: 74%

Distinct biological events generated by ECM proteolysis by two homologous collagenases

Solomonov

Zehorai

Talmi-Frank

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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It is well established that the expression profiles of multiple and possibly redundant matrix-remodeling proteases (e.g., collagenases) differ strongly in health, disease, and development. Although enzymatic redundancy might be inferred from their close similarity in structure, their in vivo activity can lead to extremely diverse tissueremodeling outcomes. We observed that proteolysis of collagen-rich natural extracellular matrix (ECM), performed uniquely by individual homologous proteases, leads to distinct events that eventually affect overall ECM morphology, viscoelastic properties, and molecular composition. We revealed striking differences in the motility and signaling patterns, morphology, and gene-expression profiles of cells interacting with natural collagen-rich ECM degraded by different collagenases. Thus, in contrast to previous notions, matrix-remodeling systems are not redundant and give rise to precise ECM-cell crosstalk. Because ECM proteolysis is an abundant biochemical process that is critical for tissue homoeostasis, these results improve our fundamental understanding its complexity and its impact on cell behavior.T he function and integrity of the extracellular matrix (ECM) is vital for cell behavior as well as for whole-tissue homeostasis (1-4). The ECM undergoes constant remodeling during health and disease states. Its components are regularly being deposited, degraded, or otherwise modified. The highly stable fibrillar collagen type I (Col I) is abundant in many organ-derived ECMs and connective tissues (5, 6); it serves as a tissue scaffold, determining ECM mechanical properties and anchoring other ECM proteins necessary for cell function (7). These processes are orchestrated by multiple remodeling enzymes, among which the matrix metalloproteinase (MMP) family plays an important role. Only a few members of this proteinase family, the collagenases, are able to degrade the resistant fibrillar collagens, i.e., Col I, as well as other ECM molecules (8, 9). The collagenases have conserved amino acids in their zinc-containing catalytic domain (8, 10) and display high structural similarities, as reflected by their functional domain organization. Nevertheless, the complex effects exerted by different MMPs on ECM and cells in vivo remain poorly understood.The enzymatic activity of MMPs, and specifically of collagenases, in vivo is tightly regulated (11), with enzymatic dysregulation causing irreversible damage associated with a variety of diseases. Abnormally elevated levels of MMP-1 or of both MMP-1 and MMP-13 have been associated with different types of cancers and with inflammatory diseases (12-21).Here, we explored the degradation patterns of natural collagenrich ECM by two homologous MMPs and tested the response of cells to intact vs. selectively degraded ECM. We collectively profiled the unique remodeling events caused by two secreted collagenases, MMP-1 and MMP-13, by using biochemical, biophysical, and proteomics tools. We show that these proteases drive morphological, biochemical, and visc...

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Section: Discussionmentioning

confidence: 74%

Distinct biological events generated by ECM proteolysis by two homologous collagenases

Solomonov

Zehorai

Talmi-Frank

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…These receptors including CXCR4, Ins(1,4,5)P3-R, and NMDA-R are not single transmembrane receptors with the exception of the discoidin domain receptor 1 (DDR1) which is a tyrosine kinase receptor activated by type I collagen (23)(24)(25)(26). The EGFR is identified as an NM II binding partner in this study.…”

Section: Discussionmentioning

confidence: 99%

“…Recent publications have reported that NM II interacts with several kinds of receptors including CXCR4 (chemokine receptor), N-methyl-D-aspartate (NMDA receptor), DDR1 (as a collagen receptor), and the Ins (1,4,5)P 3 receptor (23)(24)(25)(26). However, to date, the potential involvement of NM II in EGFRmediated intracellular signaling has not been studied in depth.…”

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confidence: 99%

Nonmuscle Myosin II Is Required for Internalization of the Epidermal Growth Factor Receptor and Modulation of Downstream Signaling

Kim

Wang

Conti

et al. 2012

Journal of Biological Chemistry

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Background: Cellular internalization of the epidermal growth factor receptor (EGFR) is essential to its downstream signaling. Results: Nonmuscle myosin II (NM II) is required for the internalization of the EGFR and modulates the EGFR-dependent activation of ERK and AKT. Conclusion: NM II binds to the EGFR, expedites internalization and helps to initiate its role in signaling. Significance: These findings elucidate an important step in the function of the EGFR.

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“…Myosin Filament Extraction-For assessment of myosin filament assembly at collagen bead sites, we used immunofluorescence methods as described previously (47). Briefly, gelsolin WT and gelsolin null cells were permeabilized by cooling to 4°C, washed with ice-cold PBS, and extracted for 30 -90 s with ice-cold 10 mM Tris, pH 7.0, 60 mM KCl, 125 mM sucrose, and 0.05% Triton X-100.…”

Section: Methodsmentioning

confidence: 99%

Gelsolin and Non-muscle Myosin IIA Interact to Mediate Calcium-regulated Collagen Phagocytosis

Arora

Wang

Janmey

et al. 2011

Journal of Biological Chemistry

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Background: Fibroblasts can remodel the extracellular matrix by phagocytosis, but how the adhesion mechanisms are regulated is not well understood. Results: Non-muscle myosin IIA provides a docking site for the actin-severing protein to localize at collagen adhesion sites and remodel actin filaments there. Conclusion: Gelsolin binds to non-muscle myosin IIA at collagen adhesions and enables phagocytosis to occur in a calciumdependent manner. Significance: Dissection of the mechanisms by which collagen phagocytosis is mediated may provide new insights into fibrotic conditions under which phagocytosis is perturbed.

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The collagen receptor DDR1 regulates cell spreading and motility by associating with myosin IIA

Cited by 85 publications

References 42 publications

Distinct biological events generated by ECM proteolysis by two homologous collagenases

Distinct biological events generated by ECM proteolysis by two homologous collagenases

Nonmuscle Myosin II Is Required for Internalization of the Epidermal Growth Factor Receptor and Modulation of Downstream Signaling

Gelsolin and Non-muscle Myosin IIA Interact to Mediate Calcium-regulated Collagen Phagocytosis

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