Cyclin Y Is Expressed in Platelets and Modulates Integrin Outside-in Signaling

Abstract

Diabetes is associated with platelet hyper-reactivity and enhanced risk of thrombosis development. Here we compared protein expression in platelets from healthy donors and diabetic patients to identify differentially expressed proteins and their possible function in platelet activation. Mass spectrometry analyses identified cyclin Y (CCNY) in platelets and its reduced expression in platelets from diabetic patients, a phenomenon that could be attributed to the increased activity of calpains. To determine the role of CCNY in platelets, mice globally lacking the protein were studied. CCNY-/- mice demonstrated lower numbers of circulating platelets but platelet responsiveness to thrombin and a thromboxane A2 analogue were comparable with that of wild-type mice, as was agonist-induced α and dense granule secretion. CCNY-deficient platelets demonstrated enhanced adhesion to fibronectin and collagen as well as an attenuated spreading and clot retraction, indicating an alteration in “outside in” integrin signalling. This phenotype was accompanied by a significant reduction in the agonist-induced tyrosine phosphorylation of β3 integrin. Taken together we have shown that CCNY is present in anucleated platelets where it is involved in the regulation of integrin-mediated outside in signalling associated with thrombin stimulation.

Cross-Sectional Gene-Smoking Interaction Analysis in Relation to Subclinical Atherosclerosis-Results From the IMPROVE Study

“…51,52 Also, levels of APOB have been noted to increase in relation to smoking tobacco, 53 however, not consistently. 54 The remaining significant results (not discussed above) from analyses based on the C-IMT max 75th or 50th percentile cutoffs, involve SNPs located in genes previously discussed in relation to: (1) regulation of cardiometabolic factors and related diseases such as obesity, hypertension and diabetes (eg, COBLL1; HFM1, CXCR1; COL21A1, DOCK3; DGKB, BMP1; IDE; KCNQ1; and KCNQ1-AS1, ZC3H10), [55][56][57][58][59][60][61][62][63][64] (2) endothelial inflammation and dysfunction (eg, TNFAIP8L1, CCNY, GSE1), [65][66][67] (3) vascular smooth muscle cell proliferation (eg, VEGFA), 68 (4) inflammatory diseases (eg, PSORS1C1), 69 (5) risk of CVD hard end point such as atrial fibrillation and venous thromboembolism (eg, ZFPM2; LMO7), 70,71 and (6) addiction behavior including nicotine dependence (eg, SP140L, THSD7B). 72,73 From the results of our analyses restricted to cell counts of 10 or below, the identification of a SNP located in the PIN2/TERF1 interacting, telomerase inhibitor 1 (PINX1) gene is potentially interesting, because this gene was previously identified in GWAS of subclinical atherosclerosis 6 and carotid plaque.…”

“…The remaining significant results (not discussed above) from analyses based on the C-IMT max 75th or 50th percentile cutoffs, involve SNPs located in genes previously discussed in relation to: (1) regulation of cardiometabolic factors and related diseases such as obesity, hypertension and diabetes (eg, COBLL1; HFM1, CXCR1; COL21A1, DOCK3; DGKB, BMP1; IDE; KCNQ1 ; and KCNQ1-AS1, ZC3H10 ), 55–64 (2) endothelial inflammation and dysfunction (eg, TNFAIP8L1 , CCNY , GSE1 ), 65–67 (3) vascular smooth muscle cell proliferation (eg, VEGFA ), 68 (4) inflammatory diseases (eg, PSORS1C1 ), 69 (5) risk of CVD hard end point such as atrial fibrillation and venous thromboembolism (eg, ZFPM2; LMO7 ), 70,71 and (6) addiction behavior including nicotine dependence (eg, SP140L, THSD7B ). 72,73…”

Molecular Research on Platelet Activity in Health and Disease 2.0

“…In addition, platelets from KO mice show increased adhesion to fibronectin and collagen, as well as attenuation of clot diffusion and retraction. Collectively, these phenomena suggest an alteration in integrin signaling “out” [ 6 ].…”