Quantitative phosphoproteomics unveils temporal dynamics of thrombin signaling in human endothelial cells

Biggelaar, Maartje van den; Hernández-Fernaud, Juan R.; Eshof, Bart L. van den; Neilson, Lisa J.; Meijer, Alexander B.; Mertens, Koenraad; Zanivan, Sara

doi:10.1182/blood-2013-12-546036

Cited by 39 publications

(37 citation statements)

References 52 publications

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Section: Basal and Regulated Secretion Of Vwfmentioning

confidence: 99%

“…57,58 However, it is fair to say that the currently accepted view is that VWF is mostly released constitutively from WPBs ( Figure 4). 14,38,39,59 When present in the endothelial cytoplasm, WPBs dance around in an undirected manner. 60 Such movements will eventually drive single WPBs to the cellular periphery, allowing them to fuse with the plasma membrane and release their contents into the extracellular space (blood or subendothelium).…”

Section: Basal and Regulated Secretion Of Vwfmentioning

confidence: 99%

“…However, in some instances, fusion of WPBs with the plasma membrane results in the selective release of WPB coresidents (interleukin-8, eotaxin-3), whereas VWF and its propeptide are retained within the cell (Figure 4). 14,38,39,61 This unexpected observation (referred to as "lingering kiss") can be explained by a sudden rise in pH of the WPB (deacidification) due to exposure to the extracellular environment. 61 This deacidification provokes a collapse of the pH-dependent tubular structure of the WPBs, thereby deforming the VWF-dependent helical structure and preventing secretion of VWF.…”

Section: Basal and Regulated Secretion Of Vwfmentioning

confidence: 99%

“…This figure has been inspired by figures presented elsewhere. 14,38,39 BLOOD, 26 MARCH 2015 x VOLUME 125, NUMBER 13 VWF BIOSYNTHESIS, SECRETION, AND CLEARANCE 2023…”

Section: Basal and Regulated Secretion Of Vwfmentioning

confidence: 99%

“…For VWF packaging into nascent organelles, a clathrin coat, the adaptor protein AP-1 and Discs Large-1 (Dlg1), appear necessary, probably to provide a scaffold and generate the typical rodshaped or cigar-like structure of the WPBs (Figure 4). 14,[38][39][40][41][42] In this regard, it should also be noted that electron tomography analysis has shown that some of the WP tubules deviate from the rod-shaped structure in that they are twisted or truncated.37,43 Finally, after being released from the Trans-Golgi network, WPBs undergo a maturation step while being anchored on filamentous actin via a triple protein complex containing Rab27a, myosin and Rab27a-interaction protein (MyRIP), and myosin Va (MyoVa). 44 …”

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confidence: 99%

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von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends

Lenting

Olivier

Denis

2015

Blood

329

336

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To understand the placement of a certain protein in a physiological system and the pathogenesis of related disorders, it is not only of interest to determine its function but also important to describe the sequential steps in its life cycle, from synthesis to secretion and ultimately its clearance. von Willebrand factor (VWF) is a particularly intriguing case in this regard because of its important auxiliary roles (both intra-and extracellular) that implicate a wide range of other proteins: its presence is required for the formation and regulated release of endothelial storage organelles, the Weibel-Palade bodies (WPBs), whereas VWF is also a key determinant in the clearance of coagulation factor VIII. Thus, understanding the molecular and cellular basis of the VWF life cycle will help us gain insight into the pathogenesis of von Willebrand disease, design alternative treatment options to prolong the factor VIII half-life, and delineate the role of VWF and coresidents of the WPBs in the prothrombotic and proinflammatory response of endothelial cells. In this review, an update on our current knowledge on VWF biosynthesis, secretion, and clearance is provided and we will discuss how they can be affected by the presence of protein defects. (Blood. 2015;125(13): 2019-2028 Introduction von Willebrand (VW) factor (VWF) is a multimeric glycoprotein present in blood plasma, the subendothelial matrix, as well as storage granules in endothelial cells (Weibel-Palade [WP] bodies [WPBs]) and platelets (a-granules).1 Although a series of novel functional properties of VWF has recently been proposed, 2 the protein is mostly known for its contribution to the hemostatic process: it mediates platelet adhesion and aggregation at sites of vascular injury and carries coagulation factor VIII (FVIII) in the circulation. 1 Patients lacking VWF manifest a severe hemorrhagic phenotype, originating from defective formation of platelet-rich thrombi and a secondary deficiency of FVIII impairing the generation of a fibrin network. Functional and/or quantitative deficiencies of VWF are known as von Willebrand disease (VWD), a disorder affecting 0.01% to 1% of the population. 3 Quantitative deficiencies of VWF result from changes in biosynthesis, secretion, and/or clearance of the protein. In this review, we will provide an overview of the current knowledge on each of these processes and we will discuss how they can be affected by the presence of protein defects. Part I: Basics of VWF biosynthesisPrimary structure VWF is produced in endothelial cells and megakaryocytes as a single prepropolypeptide of 2813 aa. The primary sequence of VWF was reported in 1986, and rapidly the presence of repeating domain structures within the protein was recognized. 4 The different domains are arranged in the order: D1-D2-D9-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2-CK, with the D1-D2 domains representing the propeptide and the remainder corresponding to the mature VWF subunit (Figure 1). [4][5][6] Progress in structural and bioinformatical analysis of protein structures...

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Section: Basal and Regulated Secretion Of Vwfmentioning

confidence: 99%

Section: Basal and Regulated Secretion Of Vwfmentioning

confidence: 99%

Section: Basal and Regulated Secretion Of Vwfmentioning

confidence: 99%

“…This figure has been inspired by figures presented elsewhere. 14,38,39 BLOOD, 26 MARCH 2015 x VOLUME 125, NUMBER 13 VWF BIOSYNTHESIS, SECRETION, AND CLEARANCE 2023…”

Section: Basal and Regulated Secretion Of Vwfmentioning

confidence: 99%

mentioning

confidence: 99%

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von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends

Lenting

Olivier

Denis

2015

Blood

329

336

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The Role of Thrombin in Brain Injury After Hemorrhagic and Ischemic Stroke

Garton

Hua

et al. 2020

Transl. Stroke Res.

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Thrombin is increased in the brain after hemorrhagic and ischemic stroke primarily due to the prothrombin entry from blood either with a hemorrhage or following blood-brain barrier disruption. Increasing evidence indicates that thrombin and its receptors (protease-activated receptors (PARs)) play a major role in brain pathology following ischemic and hemorrhagic stroke (including intracerebral, intraventricular, and subarachnoid hemorrhage). Thrombin and PARs affect brain injury via multiple mechanisms that can be detrimental or protective. The cleavage of prothrombin into thrombin is the key step of hemostasis and thrombosis which takes place in every stroke and subsequent brain injury. The extravascular effects and direct cellular interactions of thrombin are mediated by PARs (PAR-1, PAR-3, and PAR-4) and their downstream signaling in multiple brain cell types. Such effects include inducing blood-brain-barrier disruption, brain edema, neuroinflammation, and neuronal death, although low thrombin concentrations can promote cell survival. Also, thrombin directly links the coagulation system to the immune system by activating interleukin-1α. Such effects of thrombin can result in both short-term brain injury and longterm functional deficits, making extravascular thrombin an understudied therapeutic target for stroke. This review examines the role of thrombin and PARs in brain injury following hemorrhagic and ischemic stroke and the potential treatment strategies which are complicated by their role in both hemostasis and brain.

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