Platelet Signaling in Primary Haemostasis and Arterial Thrombus Formation: Part 2

Scharf, Rüdiger E.

doi:10.1055/s-0038-1675149

Cited by 18 publications

(19 citation statements)

References 65 publications

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“…Thus, vWF bridges platelet attachment to collagen even under high blood flow rates, such as observed within the arterial branch of the circulatory system (Kulkarni et al, 2000;Hansen et al, 2018). Moreover, the GPIbcomplex-mediated attachment of platelets to vWF and collagen under high shear forces results in stretching of the GPIb-chain and thus triggers an activating signal which is further transduced via the phosphoprotein-binding adaptor protein 14-3-3 within the platelet (Chen et al, 2018;Scharf, 2018b;Quach and Li, 2020).…”

Section: Platelets the Cellular Players In Hemostasismentioning

confidence: 99%

Platelets, Constant and Cooperative Companions of Sessile and Disseminating Tumor Cells, Crucially Contribute to the Tumor Microenvironment

Obermann

Brockhaus

Eble

2021

Front. Cell Dev. Biol.

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Although platelets and the coagulation factors are components of the blood system, they become part of and contribute to the tumor microenvironment (TME) not only within a solid tumor mass, but also within a hematogenous micrometastasis on its way through the blood stream to the metastatic niche. The latter basically consists of blood-borne cancer cells which are in close association with platelets. At the site of the primary tumor, the blood components reach the TME via leaky blood vessels, whose permeability is increased by tumor-secreted growth factors, by incomplete angiogenic sprouts or by vasculogenic mimicry (VM) vessels. As a consequence, platelets reach the primary tumor via several cell adhesion molecules (CAMs). Moreover, clotting factor VII from the blood associates with tissue factor (TF) that is abundantly expressed on cancer cells. This extrinsic tenase complex turns on the coagulation cascade, which encompasses the activation of thrombin and conversion of soluble fibrinogen into insoluble fibrin. The presence of platelets and their release of growth factors, as well as fibrin deposition changes the TME of a solid tumor mass substantially, thereby promoting tumor progression. Disseminating cancer cells that circulate in the blood stream also recruit platelets, primarily by direct cell-cell interactions via different receptor-counterreceptor pairs and indirectly by fibrin, which bridges the two cell types via different integrin receptors. These tumor cell-platelet aggregates are hematogenous micrometastases, in which platelets and fibrin constitute a particular TME in favor of the cancer cells. Even at the distant site of settlement, the accompanying platelets help the tumor cell to attach and to grow into metastases. Understanding the close liaison of cancer cells with platelets and coagulation factors that change the TME during tumor progression and spreading will help to curb different steps of the metastatic cascade and may help to reduce tumor-induced thrombosis.

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Section: Platelets the Cellular Players In Hemostasismentioning

confidence: 99%

Platelets, Constant and Cooperative Companions of Sessile and Disseminating Tumor Cells, Crucially Contribute to the Tumor Microenvironment

Obermann

Brockhaus

Eble

2021

Front. Cell Dev. Biol.

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“…Platelets are small anucleated fragments derived from megakaryocytes in bone marrow sinusoids, circulating in the blood. Upon vascular injury, subendothelial matrix proteins, such as collagen are exposed to the blood flow, anchoring von-Willebrand-Factor (vWF) and initiating platelet glycoprotein (GP)Ibα-vWF interaction and subsequent GPVI-collagen interaction, a crucial step in platelet activation [11][12][13][14]. Activated platelets express various integrins in their active conformation.…”

Section: Regulation Of Platelet Receptor Function By N-glycosylationmentioning

confidence: 99%

Platelets and Defective N-Glycosylation

Mammadova‐Bach

Jaeken

Gudermann

et al. 2020

IJMS

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N-glycans are covalently linked to an asparagine residue in a simple acceptor sequence of proteins, called a sequon. This modification is important for protein folding, enhancing thermodynamic stability, and decreasing abnormal protein aggregation within the endoplasmic reticulum (ER), for the lifetime and for the subcellular localization of proteins besides other functions. Hypoglycosylation is the hallmark of a group of rare genetic diseases called congenital disorders of glycosylation (CDG). These diseases are due to defects in glycan synthesis, processing, and attachment to proteins and lipids, thereby modifying signaling functions and metabolic pathways. Defects in N-glycosylation and O-glycosylation constitute the largest CDG groups. Clotting and anticlotting factor defects as well as a tendency to thrombosis or bleeding have been described in CDG patients. However, N-glycosylation of platelet proteins has been poorly investigated in CDG. In this review, we highlight normal and deficient N-glycosylation of platelet-derived molecules and discuss the involvement of platelets in the congenital disorders of N-glycosylation.

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“…Exposure of the circulating platelets to collagen and von Willebrand factor derived from the damaged endothelial cells turns on integrin inside-out signaling leading to an increase in the binding affinity of integrin αIIbβ3 to soluble fibrinogen [2]. Fibrinogen binding further activates integrin αIIbβ3 outside-in signaling that subsequently causes cytoskeletal remodeling and clot retraction to prevent blood loss [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

“…The agonists of thrombin, thromboxane A2 (TXA2), and ADP bind to their respective G protein-coupled receptors and activate either a G αq -dependent increase in intracellular calcium and protein kinase C (PKC) activity, G α12/13 -dependent Rho activation, G αi -dependent inhibition of adenylyl cyclase, and/or G βγ -dependent phosphoinositide 3-kinase-Akt activation [2,3,[6][7][8]. Collagen interacts with glycoprotein VI and recruits Src and Syk to the plasma membrane followed by tyrosine phosphorylation of downstream substrates required for platelet activation [3,9]. The phosphorylation and talin binding cause conformational change of the receptor and transform integrin from the resting to the active stage, which elicits high affinity binding activity to fibrinogen.…”

Section: Introductionmentioning

confidence: 99%

Integrin αIIbβ3 outside-in signaling activates human platelets through serine 24 phosphorylation of Disabled-2

et al. 2021

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Background Bidirectional integrin αIIbβ3 signaling is essential for platelet activation. The platelet adaptor protein Disabled-2 (Dab2) is a key regulator of integrin signaling and is phosphorylated at serine 24 in eukaryotic cells. However, the mechanistic insight and function of Dab2-serine 24 phosphorylation (Dab2-pSer24) in platelet biology are barely understood. This study aimed to define whether and how Dab2 is phosphorylated at Ser24 during platelet activation and to investigate the effect of Dab2-pSer24 on platelet function. Results An antibody with confirmed specificity for Dab2-pSer24 was generated. By using this antibody as a tool, we showed that protein kinase C (PKC)-mediated Dab2-pSer24 was a conservative signaling event when human platelets were activated by the platelet agonists such as thrombin, collagen, ADP, 12-O-tetradecanoylphorbol-13-acetate, and the thromboxane A2 activator U46619. The agonists-stimulated Dab2-pSer24 was attenuated by pretreatment of platelets with the RGDS peptide which inhibits integrin outside-in signaling by competitive binding of integrin αIIb with fibrinogen. Direct activation of platelet integrin outside-in signaling by combined treatment of platelets with manganese dichloride and fibrinogen or by spreading of platelets on fibrinogen also resulted in Dab2-pSer24. These findings implicate that Dab2-pSer24 was associated with the outside-in signaling of integrin. Further analysis revealed that Dab2-pSer24 was downstream of Src-PKC-axis and phospholipase D1 underlying the integrin αIIbβ3 outside-in signaling. A membrane penetrating peptide R11-Ser24 which contained 11 repeats of arginine linked to the Dab2-Ser24 phosphorylation site and its flanking sequences (RRRRRRRRRRR19APKAPSKKEKK29) and the R11-S24A peptide with Ser24Ala mutation were designed to elucidate the functions of Dab2-pSer24. R11-Ser24 but not R11-S24A inhibited agonists-stimulated Dab2-pSer24 and consequently suppressed platelet spreading on fibrinogen, with no effect on platelet aggregation and fibrinogen binding. Notably, Ser24 and the previously reported Ser723 phosphorylation (Dab2-pSer723) occurred exclusively in a single Dab2 molecule and resulted in distinctive subcellular distribution and function of Dab2. Dab2-pSer723 was mainly distributed in the cytosol of activated platelets and associated with integrin inside-out signaling, while Dab2-pSer24 was mainly distributed in the membrane fraction of activated platelets and associated with integrin outside-in signaling. Conclusions These findings demonstrate for the first time that Dab2-pSer24 is conservative in integrin αIIbβ3 outside-in signaling during platelet activation and plays a novel role in the control of cytoskeleton reorganization and platelet spreading on fibrinogen.

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Platelet Signaling in Primary Haemostasis and Arterial Thrombus Formation: Part 2

Cited by 18 publications

References 65 publications

Platelets, Constant and Cooperative Companions of Sessile and Disseminating Tumor Cells, Crucially Contribute to the Tumor Microenvironment

Platelets, Constant and Cooperative Companions of Sessile and Disseminating Tumor Cells, Crucially Contribute to the Tumor Microenvironment

Platelets and Defective N-Glycosylation

Integrin αIIbβ3 outside-in signaling activates human platelets through serine 24 phosphorylation of Disabled-2

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