Mice Lacking PECAM-1 and Ceacam1 Have Enhanced Platelet Secretion and Thrombus Growth: Novel Link with PAR4

Kuriri, Fahd A.; Burchall, Genia; Alanazi, Fehaid; Antonipillai, Juliana; Dobie, Gasim; Beauchemin, Nicole; Jackson, Denise E.

doi:10.1055/a-1663-8108

Cited by 3 publications

(2 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In vivo, one could argue about the effect of lack of PECAM-1 in platelets and the role of blood clot formation for melanoma cell extravasation. Platelet counts were found to be comparable between PECAM-1-ko and control mice [55]. The role of platelet PECAM-1 in thrombus formation in response to stimulation by a variety of agonists has not been conclusively established, as one report describes a rather minor or negligible role [56], while two other studies reported increased thrombus formation in PECAM-1-ko mice [57,58].…”

Section: Discussionmentioning

confidence: 92%

Compromised Blood-Brain Barrier Junctions Enhance Melanoma Cell Intercalation and Extravasation

Saltarin,

Wegmüller,

Bejarano

et al. 2023

Cancers

View full text Add to dashboard Cite

Melanoma frequently metastasises to the brain, and a detailed understanding of the molecular and cellular mechanisms underlying melanoma cell extravasation across the blood-brain barrier (BBB) is important for preventing brain metastasis formation. Making use of primary mouse brain microvascular endothelial cells (pMBMECs) as an in vitro BBB model, we imaged the interaction of melanoma cells into pMBMEC monolayers. We observed exclusive junctional intercalation of melanoma cells and confirmed that melanoma-induced pMBMEC barrier disruption can be rescued by protease inhibition. Interleukin (IL)-1β stimulated pMBMECs or PECAM-1-knockout (-ko) pMBMECs were employed to model compromised BBB barrier properties in vitro and to determine increased melanoma cell intercalation compared to pMBMECs with intact junctions. The newly generated brain-homing melanoma cell line YUMM1.1-BrM4 was used to reveal increased in vivo extravasation of melanoma cells across the BBB of barrier-compromised PECAM-1-deficient mice compared to controls. Taken together, our data indicate that preserving BBB integrity is an important measure to limit the formation of melanoma-brain metastasis.

show abstract

Section: Discussionmentioning

confidence: 92%

Compromised Blood-Brain Barrier Junctions Enhance Melanoma Cell Intercalation and Extravasation

Saltarin,

Wegmüller,

Bejarano

et al. 2023

Cancers

View full text Add to dashboard Cite

show abstract

“…Thus, other ITIM-linked receptors on platelets such as PECAM1 and CEACAM1/2 are able to regulate outside-in signaling [28,29]. These types of effects will depend on the nature of the receptor engagement duration, avidity, affinity, and clustering [30]. Overall, our findings are suggestive of a dual feature of perlecan's core structure-which is also present in endorepellin-to act on one hand as a ligand for platelet integrins and, on the other hand, as a modulating agent of signaling platelet collagen receptors.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Glycoprotein VI-Dependent Platelet Activation and Thrombus Formation by Heparan Sulfate Proteoglycan Perlecan

Provenzale,

De Simone,

Gibbins

et al. 2023

IJMS

View full text Add to dashboard Cite

Proteoglycans form a heterogeneous family of proteins with covalently bound sulfated glycosaminoglycans. The extracellular matrix proteoglycan perlecan has been proposed to bind to the platelet- and megakaryocyte-specific receptor G6bB, co-regulating platelet glycoprotein VI (GPVI) signaling. The derived non-sulfate proteoglycan endorepellin was previously shown to enhance platelet adhesion via the collagen receptor, integrin α2β1. Here, we compared the roles of perlecan and other matrix proteoglycans in platelet responses and thrombus formation. We used multi-color flow cytometry to measure the degranulation and integrin αIIbβ3 activation of washed platelets in response to various proteoglycans and collagen-related peptide (CRP), the GPVI agonist. Perlecan, but not endorepellin, enhanced the CRP-induced activation of platelets in a time- and concentration-dependent manner. Similar to collagen, immobilized perlecan, but not other proteoglycans, supported static platelet adhesion and spreading. In-flowed whole-blood perlecan diminished shear-dependent platelet adhesion, while it enforced GPVI-dependent thrombus formation—to a larger extent than endorepellin—to induce more contracted aggregates of activated platelets. We concluded that the sulfated proteoglycan perlecan enhances GPVI-dependent platelet responses extending to thrombus formation, but it does so at the expense of reduced adhesion of platelets under flow.

show abstract

Protease-activated receptors in health and disease

Peach

Edgington-Mitchell

Bunnett

et al. 2023

Physiological Reviews

View full text Add to dashboard Cite

Although generally regarded as degradatory enzymes, certain proteases are also signaling molecules that specifically control cellular functions by cleaving protease-activated receptors (PARs). The four known PARs are members of the large family of G protein-coupled receptors. These transmembrane receptors control most physiological and pathological processes and are the target of a large proportion of therapeutic drugs. Signaling proteases include enzymes from the circulation, from immune, inflammatory epithelial and cancer cells, as well as from commensal and pathogenic bacteria. Advances in our understanding of the structure and function of PARs provide insights into how diverse proteases activate these receptors to regulate physiological and pathological processes in most tissues and organ systems. The realization that proteases and PARs are key mediators of disease, coupled with advances in understanding the atomic level structure of PARs and their mechanisms of signaling in subcellular microdomains, has spurred the development of antagonists, some of which have advanced to the clinic. Herein we review the discovery, structure and function of this receptor system, highlight the contribution of PARs to homeostatic control, and discuss the potential of PAR antagonists for the treatment of major diseases.

show abstract

Mice Lacking PECAM-1 and Ceacam1 Have Enhanced Platelet Secretion and Thrombus Growth: Novel Link with PAR4

Cited by 3 publications

References 41 publications

Compromised Blood-Brain Barrier Junctions Enhance Melanoma Cell Intercalation and Extravasation

Compromised Blood-Brain Barrier Junctions Enhance Melanoma Cell Intercalation and Extravasation

Regulation of Glycoprotein VI-Dependent Platelet Activation and Thrombus Formation by Heparan Sulfate Proteoglycan Perlecan

Protease-activated receptors in health and disease

Contact Info

Product

Resources

About