The non‐transmembrane phosphotyrosine phosphatase 1B (PTP‐1B) is an abundant enzyme, normally localized to the cytosolic face of the endoplasmic reticulum via a C‐terminal targeting sequence. We have found that agonist‐induced platelet activation results in proteolytic cleavage of PTP‐1B at a site upstream from this targeting sequence, causing subcellular relocation of its catalytic domain from membranes to the cytosol. PTP‐1B cleavage is catalyzed by the calcium‐dependent neutral protease calpain and is a general feature of platelet agonist‐induced aggregation. Moreover, PTP‐1B cleavage correlates with the transition from reversible to irreversible platelet aggregation in platelet‐rich plasma. Engagement of gpIIb‐IIIa is necessary for inducing PTP‐1B cleavage, suggesting that integrins regulate tyrosine phosphatases as well as tyrosine kinases. PTP‐1B cleavage is accompanied by a 2‐fold stimulation of its enzymatic activity, as measured by immune complex phosphatase assay, and correlates with discrete changes in the pattern of tyrosyl phosphorylation. Cleavage and subcellular relocation of PTP‐1B represents a novel mechanism for altering tyrosyl phosphorylation that may have important physiological implications in cell types other than platelets.
A B S T R A C T Porcine intestinal mucosal heparin induced aggregation of platelets in citrated platelet-rich plasma and enhanced platelet aggregation and serotonin secretion induced by other agents. This action ofheparin was blocked by substances that elevate platelet cyclic AMP and by EDTA but not by inhibitors of platelet cyclooxygenase. The effect was not inhibited by apyrase or by N-amylthio-5'-AMP and therefore did not require the action of ADP, nor was there activation of platelet phospholipase. Platelet aggregation by heparin required a plasma cofactor different from the cofactor required for ristocetin.Fractionation of heparin yielded preparations that varied in molecular weight and, within a given molecular weight fraction, in affinity for antithrombin III.Fractions of high molecular weight (average 20,000) were more reactive with platelets than were fractions of low molecular weight (7,000). Anticoagulant activity did not parallel the platelet reactivity of heparin fractions. Among high molecular weight fractions, preparations of high or low antithrombin affinity were equally active in induction of platelet aggregation. In low molecular weight fractions, there was an inverse relationship between platelet reactivity and anticoagulant activity in normal platelet-rich plasma, but, in plateletrich plasma depleted of antithrombin, low molecular weight fractions of high and low antithrombin affinity reacted equally with platelets. These results suggest that formation of an antithrombin-heparin complex protected platelets from aggregation by heparin.Selection of heparin fractions of low molecular weight and high antithrombin affinity may improve anticoagulant therapy and development of thromboresistant heparin-coated artificial materials.
No abstract
Suspensions of human red cells in citrated plasma, in Ringer solution, and in Ringer solution containing albumin were passed through straight and curved glass and plastic hollow fibers (diameter range, 100–1,000 μ). Pressure-flow relations were measured over the pressure range of 0.1– 800 mm water, corresponding to a shear stress range of 0.01– 80 dynes/cm2. The suspensions were tested simultaneously in a rotational viscometer. It was found that red cell suspensions exhibit a yield shear stress only if the plasma protein fibrinogen is present. Experimental pressure-flow data in hollow fibers were in excellent agreement with rotational viscometer measurements and with analytical predictions based on the assumptions that blood flows as a homogeneous continuum and that the velocity at the wall is zero. Effects of tube surface characteristics and curvature on the pressure drop-flow rate relation were not discernible. microcirculation models; model blood flow; yield stress of blood; capillary blood flow and viscometry; fibrinogen and blood flow in hollow fibers; non-Newtonian flow of blood in hollow fibers Submitted on July 20, 1964
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