Distinct Kinetic and Molecular Requirements Govern CD44 Binding to Hyaluronan versus Fibrin(ogen)

Raman, Phrabha S.; Alves, Christina; Wirtz, Denis; Κωνσταντόπουλος, Κωνσταντίνος

doi:10.1016/j.bpj.2012.06.039

Cited by 25 publications

(36 citation statements)

References 43 publications

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“…AFM-based force spectroscopy demonstrated physical binding between HA and CD44 with rupture force between 60 and 90 pN, which is similar to forces needed to unbind integrin–ligand complexes. 22,23 Hyaluronic acid is a large, linear, negatively charged macromolecule that forms viscous liquids and cross-linked 3D structures and is believed to play a structural role in brain ECM formation and function. Its role in mechanical properties of the brain is not fully understood, but in other materials like cartilage it acts to retain water and resist compression while allowing compliance in shear.…”

Section: Introductionmentioning

confidence: 99%

Soft Substrates Containing Hyaluronan Mimic the Effects of Increased Stiffness on Morphology, Motility, and Proliferation of Glioma Cells

et al. 2017

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Unlike many other cancer cells that grow in tumors characterized by an abnormally stiff collagen-enriched stroma, glioma cells proliferate and migrate in the much softer environment of the brain, which generally lacks the filamentous protein matrix characteristic of breast, liver, colorectal, and other types of cancer. Glial cell-derived tumors and the cells derived from them are highly heterogeneous and variable in their mechanical properties, their response to treatments, and their properties in vitro. Some glioma samples are stiffer than normal brain when measured ex vivo, but even those that are soft in vitro stiffen after deformation by pressure gradients that arise in the tumor environment in vivo. Such mechanical differences can strongly alter the phenotype of cultured glioma cells. Alternatively, chemical signaling might elicit the same phenotype as increased stiffness by activating intracellular messengers common to both initial stimuli. In this study the responses of three different human glioma cell lines to changes in substrate stiffness are compared with their responses on very soft substrates composed of a combination of hyaluronic acid and a specific integrin ligand, either laminin or collagen I. By quantifying cell morphology, stiffness, motility, proliferation, and secretion of the cytokine IL-8, glioma cell responses to increased stiffness are shown to be nearly identically elicited by substrates containing hyaluronic acid, even in the absence of increased stiffness. PI3-kinase activity was required for the response to hyaluronan but not to stiffness. This outcome suggests that hyaluronic acid can trigger the same cellular response, as can be obtained by mechanical force transduced from a stiff environment, and demonstrates that chemical and mechanical features of the tumor microenvironment can achieve equivalent reactions in cancer cells.

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Section: Introductionmentioning

confidence: 99%

Soft Substrates Containing Hyaluronan Mimic the Effects of Increased Stiffness on Morphology, Motility, and Proliferation of Glioma Cells

et al. 2017

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“…These kinetic and micromechanical properties of PODXL-E-selectin bond facilitate cell rolling on E-selectin over a range of shear stresses provided that the timescale of the interaction is long enough to allow a sufficient number of bonds to form, overcoming the shear force on the cell (1,28). In contrast, the CD44v-HA bond has a k off°o f 0.005 s 21 , indicating that the bond has a longer bond lifetime in the absence of force, and a x b of 0.59 nm, indicating that the bond is more susceptible to rupture in the presence of force than the PODXL-E-selectin bond (12). Although selectin-ligand binding mediates rolling interactions (34)(35)(36), the kinetic properties of the CD44v-HA bond contribute to the slow rolling and stationary adhesion observed for CD44-expressing cells binding to HA at low shear stresses (12,18,19).…”

Section: Discussionmentioning

confidence: 99%

“…The f/t was set to be 689 pN/dyn-cm 2 , assuming the cell is behaving more like a neutrophil than a bead (29), and considering the Pa03c cell radius, which was measured to be 10.1 6 2.6 mm. The kinetic constants for the CD44v-HA bond used were k off°= 0.005 s 21 and x b = 0.59 nm, determined via single-molecule force spectroscopy (12).…”

Section: Mathematical Model Of 2-d Selectin-mediated Cell Adhesion Onmentioning

confidence: 99%

“…CD44, expressed on Pa03c pancreatic cancer cells (Supplemental Fig. S1), is the major counterreceptor for HA (12)(13)(14) and has been implicated in pancreatic cancer metastasis (15). HA binding to CD44 has been shown to increase cancer invasion and metastasis (16,17).…”

mentioning

confidence: 99%

“…HA binding to CD44 has been shown to increase cancer invasion and metastasis (16,17). Specifically, the HA-CD44 bond can initiate slow cell rolling (12,18,19) and mediate stationary (firm) adhesion at low shear stresses (18,19).…”

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confidence: 99%

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E‐selectin‐mediated rolling facilitates pancreatic cancer cell adhesion to hyaluronic acid

Shea¹,

Li²,

Stebe³

et al. 2017

FASEB j.

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Tumor cell extravasation is a multistep process preceded by cell rolling and arrest on the vessel wall the formation of specific receptor-ligand bonds. The strength, availability, and number of receptor-ligand bonds regulate the rate by which tumor cells tether, roll, and adhere to vascular walls. Although the mechanics of selectin-mediated rolling have been extensively studied, little is known regarding how tumor cell rolling on selectins facilitates adhesion to a distinct substrate-bound protein with different kinetic properties. By using multicomponent protein patterning and a microfluidic system, we evaluated how E-selectin-dependent rolling modulates hyaluronic acid (HA) adhesion as a function of fluid shear, contact time, and the spacing between E-selectin and HA regions patterned on the substrate. We show that tumor cells rolling on E-selectin were ∼40-fold more likely to bind to HA than nonrolling cells in shear flow. Furthermore, E-selectin-dependent rolling promotes adhesion to HA by both physically slowing cells and enabling them to position proximal to the surface, thereby increasing the on rate of adhesion. A better understanding of tumor cell adhesion under physiologic shear would lead to the development of new diagnostic assays and pave the way to clinical approaches aimed ultimately to halt metastasis.-Shea, D. J., Li, Y. W., Stebe, K. J., Konstantopoulos, K. E-selectin-mediated rolling facilitates pancreatic cancer cell adhesion to hyaluronic acid.

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Biochemical determinants of the IGFBP‐3–hyaluronan interaction

et al. 2020

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IGFBP‐3, the most abundant IGFBP and the main carrier of insulin‐like growth factor I (IGF‐I) in the circulation, can bind IGF‐1 with high affinity, which attenuates IGF/IGF‐IR interactions, thereby resulting in antiproliferative effects. The C‐terminal domain of insulin‐like growth factor‐binding protein‐3 (IGFBP‐3) is known to contain an 18‐basic amino acid motif capable of interacting with either humanin (HN) or hyaluronan (HA). We previously showed that the 18‐amino acid IGFBP‐3 peptide is capable of binding either HA or HN with comparable affinities to the full‐length IGFBP‐3 protein and that IGFBP‐3 can compete with the HA receptor, CD44, for binding HA. Blocking the interaction between HA and CD44 reduced viability of A549 human lung cancer cells. In this study, we set out to better characterize IGFBP‐3‐HA interactions. We show that both stereochemistry and amino acid identity are important determinants of the interaction between the IGFBP‐3 peptide and HA and for the peptide's ability to exert its cytotoxic effects. Binding of IGFBP‐3 to either HA or HN was unaffected by glycosylation or reduction of IGFBP‐3, suggesting that the basic 18‐amino acid residue sequence of IGFBP‐3 remains accessible for interaction with either HN or HA upon glycosylation or reduction of the full‐length protein. Removing N‐linked oligosaccharides from CD44 increased its ability to compete with IGFBP‐3 for binding HA, while reduction of CD44 rendered the protein relatively ineffective at blocking IGFBP‐3‐HA interactions. We conclude that both deglycosylation and disulfide bond formation are important for CD44 to compete with IGFBP‐3 for binding HA.

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Distinct Kinetic and Molecular Requirements Govern CD44 Binding to Hyaluronan versus Fibrin(ogen)

Cited by 25 publications

References 43 publications

Soft Substrates Containing Hyaluronan Mimic the Effects of Increased Stiffness on Morphology, Motility, and Proliferation of Glioma Cells

Soft Substrates Containing Hyaluronan Mimic the Effects of Increased Stiffness on Morphology, Motility, and Proliferation of Glioma Cells

E‐selectin‐mediated rolling facilitates pancreatic cancer cell adhesion to hyaluronic acid

Biochemical determinants of the IGFBP‐3–hyaluronan interaction

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