Secreted modular calcium-binding protein 1 binds and activates thrombin to account for platelet hyperreactivity in diabetes

Blood ◽  
2021 ◽  
Vol 137 (12) ◽  
pp. 1641-1651
Author(s):  
Fredy Delgado Lagos ◽  
Amro Elgheznawy ◽  
Anastasia Kyselova ◽  
Dagmar Meyer zu Heringdorf ◽  
Corina Ratiu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Monoclonal Antibodies ◽  
Platelet Function ◽  
Calcium Binding ◽  
Transforming Growth Factor ◽  
Binding Protein ◽  
Calcium Binding Protein ◽  
Matricellular Protein

Abstract Secreted modular calcium-binding protein 1 (SMOC1) is an osteonectin/SPARC-related matricellular protein, whose expression is regulated by microRNA-223 (miR-223). Given that platelets are rich in miR-223, this study investigated the expression of SMOC1 and its contribution to platelet function. Human and murine platelets expressed SMOC1, whereas platelets from SMOC1+/− mice did not present detectable mature SMOC1 protein. Platelets from SMOC1+/− mice demonstrated attenuated responsiveness to thrombin (platelet neutrophil aggregate formation, aggregation, clot formation, Ca2+ increase, and β3 integrin phosphorylation), whereas responses to other platelet agonists were unaffected. SMOC1 has been implicated in transforming growth factor-β signaling, but no link to this pathway was detected in platelets. Rather, the SMOC1 Kazal domain directly bound thrombin to potentiate its activity in vitro, as well as its actions on isolated platelets. The latter effects were prevented by monoclonal antibodies against SMOC1. Platelets from miR-223–deficient mice expressed high levels of SMOC1 and exhibited hyperreactivity to thrombin that was also reversed by preincubation with monoclonal antibodies against SMOC1. Similarly, SMOC1 levels were markedly upregulated in platelets from individuals with type 2 diabetes, and the SMOC1 antibody abrogated platelet hyperresponsiveness to thrombin. Taken together, we have identified SMOC1 as a novel thrombin-activating protein that makes a significant contribution to the pathophysiological changes in platelet function associated with type 2 diabetes. Thus, strategies that target SMOC1 or its interaction with thrombin may be attractive therapeutic approaches to normalize platelet function in diabetes.

scholarly journals Calcium Binding Protein S100A16 Expedites Proliferation, Invasion and EMT Process in Gastric Cancer

2021 ◽  
Author(s):  
Xiaoying You ◽  
Min Li ◽  
Hongwei Cai ◽  
Wenwen Zhang ◽  
Ye Hong ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Molecular Mechanism ◽  
Calcium Binding ◽  
Malignant Tumors ◽  
Binding Protein ◽  
Calcium Binding Protein ◽  
Tumor Formation ◽  
Mesenchymal Transition

Abstract Background: Gastric cancer (GC) is one of the most common malignant tumors of the digestive system, which has been the second cause of cancer-related deaths worldwide. The distant metastasis is one of the main reasons for the high recurrence and mortality rate of GC patients. Hence, it is necessary to investigate the molecular mechanism underlying gastric carcinogenesis and progression, especially the key genes and signaling pathways that promote GC cells proliferation, invasion, and metastasis. Methods: Using bioinformatics and clinicopathological analysis, in vivo tumor formation assays, mass spectrometry and so on, we characterized the role and molecular mechanism of S100 Calcium Binding Protein A16 (S100A16) in promoting GC tumor growth, migration, invasion and epithelial-to-mesenchymal transition (EMT), and investigated how Zonula Occludens-2 (ZO-2) inhibition mediates S100A16-induced metastasis and progression in GC.Results: We analyzed S100A16 expression with the GEPIA database and the UALCAN cancer database, and the prognostic analysis was performed using 100 clinical GC samples. We found that S100A16 is significantly upregulated in GC tissues and closely correlated with poor prognosis in GC patients. Functional studies reveal that S100A16 overexpression triggers GC cells proliferation and migration both in vivo and in vitro; by contrast, S100A16 knockdown restricts the speed of GC cells growth and mobility. Proteomic analysis results reveal a large S100A16 interactome, which includes ZO-2, a master regulator of cell-to-cell tight junctions. Mechanistic assay results indicate that excessive S100A16 instigates GC cell invasion, migration and EMT via ZO-2 inhibition, which arose from S100A16-mediated ZO-2 ubiquitination and degradation. Conclusions: Our results not only reveal that S100A16 is a promising candidate biomarker in GC early diagnosis and prediction of metastasis, but also establish the therapeutic importance of targeting S100A16 in order to prevent ZO-2 loss and suppress GC metastasis and progression.

scholarly journals The Calcium-Binding Protein EFhd2 Modulates Synapse Formation In Vitro and Is Linked to Human Dementia

2014 ◽  
Vol 73 (12) ◽  
pp. 1166-1182 ◽  
Author(s):  
Eva Borger ◽  
Abigail Herrmann ◽  
David A. Mann ◽  
Tara Spires-Jones ◽  
Frank Gunn-Moore
Keyword(s):  
Calcium Binding ◽  
Synapse Formation ◽  
Binding Protein ◽  
Calcium Binding Protein

In vitro enzyme activation with calbindin-D28k, the vitamin D-dependent 28 kDa calcium binding protein

FEBS Letters ◽  
1992 ◽  
Vol 297 (1-2) ◽  
pp. 127-131 ◽  
Author(s):  
Peter D. Reisner ◽  
Sylvia Christakos ◽  
Thomas C. Vanaman
Keyword(s):  
Vitamin D ◽  
Calcium Binding ◽  
Binding Protein ◽  
Calcium Binding Protein ◽  
Enzyme Activation ◽  
Calbindin D28k

Immunohistochemical localization of S100 beta in human nervous system tumors by using monoclonal antibodies with specificity for the S100 beta polypeptide.

1986 ◽  
Vol 34 (8) ◽  
pp. 977-982 ◽  
Author(s):  
L J Van Eldik ◽  
R A Jensen ◽  
B A Ehrenfried ◽  
W O Whetsell
Keyword(s):  
Monoclonal Antibody ◽  
Nervous System ◽  
Monoclonal Antibodies ◽  
Calcium Binding ◽  
Binding Protein ◽  
Immunohistochemical Localization ◽  
Calcium Binding Protein ◽  
Nervous System Tumors ◽  
Human Nervous System

The immunohistochemical localization of the calcium-binding protein, S100 beta, in human nervous system tumors has been examined by using a monoclonal antibody with specificity for the S100 beta polypeptide. S100 beta-specific immunoreactivity is detected in astrocytoma, glioblastoma, Schwannoma, ependymoma, and craniopharyngioma, whereas no reactivity is seen in oligodendroglioma, meningioma, neuroblastoma, or medulloblastoma. These data suggest that analysis of S100 beta localization with these monoclonal antibodies may be useful for research or diagnostic purposes.

scholarly journals Calcium Binding Protein S100A16 Expedites Proliferation, Invasion and Epithelial-Mesenchymal Transition Process in Gastric Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaoying You ◽  
Min Li ◽  
Hongwei Cai ◽  
Wenwen Zhang ◽  
Ye Hong ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Calcium Binding ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Tumors ◽  
Binding Protein ◽  
Transition Process ◽  
Calcium Binding Protein ◽  
Mesenchymal Transition

Gastric cancer (GC) is one of the most common malignant tumors of the digestive system, listed as the second cause of cancer-related deaths worldwide. S100 Calcium Binding Protein A16 (S100A16) is an acidic calcium-binding protein associated with several types of tumor progression. However, the function of S100A16 in GC is still not very clear. In this study, we analyzed S100A16 expression with the GEPIA database and the UALCAN cancer database. Meanwhile, 100 clinical GC samples were used for the evaluation of its role in the prognostic analysis. We found that S100A16 is significantly upregulated in GC tissues and closely correlated with poor prognosis in GC patients. Functional studies reveal that S100A16 overexpression triggers GC cell proliferation and migration both in vivo and in vitro; by contrast, S100A16 knockdown restricts the speed of GC cell growth and mobility. Proteomic analysis results reveal a large S100A16 interactome, which includes ZO-2 (Zonula Occludens-2), a master regulator of cell-to-cell tight junctions. Mechanistic assay results indicate that excessive S100A16 instigates GC cell invasion, migration, and epithelial-mesenchymal transition (EMT) via ZO-2 inhibition, which arose from S100A16-mediated ZO-2 ubiquitination and degradation. Our results not only reveal that S100A16 is a promising candidate biomarker in GC early diagnosis and prediction of metastasis, but also establish the therapeutic importance of targeting S100A16 to prevent ZO-2 loss and suppress GC metastasis and progression.

scholarly journals Neutrophils and the calcium-binding protein MRP-14 mediate carrageenan-induced antinociception in mice

2002 ◽  
Vol 11 (4) ◽  
pp. 203-210 ◽  
Author(s):  
Rosana L. Pagano ◽  
Maria Angela Amorim Dias ◽  
Camila S. Dale ◽  
Renata Giorgi
Keyword(s):  
Monoclonal Antibodies ◽  
Calcium Binding ◽  
Inflammatory Pain ◽  
Binding Protein ◽  
Peritoneal Macrophages ◽  
Calcium Binding Protein ◽  
Endogenous Opioids ◽  
Nociceptive Response ◽  
Simultaneous Treatment ◽  
Significant Expression

Background: We have previously shown that the calcium-binding protein MRP-14 secreted by neutrophils mediates the antinociceptive response in an acute inflammatory model induced by the intraperitoneal injection of glycogen in mice.Aim: In an attempt to broaden the concept that neutrophils and MRP-14 controls inflammatory pain induced by different type of irritants, in the present study, after demonstrating that carrageenan (Cg) also induces atinociception in mice, we investigated the participation of both neutrophils and MRP-14 in the phenomenon.Methods: Male Swiss mice were injected intraperitoneally with Cg and after different time intervals, the pattern of cell migration of the peritoneal exudate and the nociceptive response of animals submitted to the writhing test were evaluated. The participation of neutrophils and of the MRP-14 on the Cg effect was evaluated by systemic inoculation of monoclonal antibodies anti-granulocyte and anti-MRP-14.Results: Our results demonstrate that the acute neutrophilic peritonitis evoked by Cg induced antinociception 2, 4 and 8 h after inoculation of the irritant. Monoclonal antibodies anti-granulocyte or anti-MRP-14 reverts the antinociceptive response only 2 and 8 h after Cg injection. The antibody anti-MRP-14 partially reverts the antinociception observed after 4 h of Cg injection while the anti-granulocyte antibody enhances this effect. This effect is reverted by simultaneous treatment of the animals with both antibodies. After 4 h of Cg injection in neutrophil-depleted mice a significant expression of the calcium-binding protein MRP-14 was detected in the cytoplasm of peritoneal macrophages. This suggests that the enhancement of the effect observed after treatment with the anti-neutrophil antibody may be due to secretion of MRP-14 by macrophages. It has also been demonstrated that endogenous opioids and glucocorticoids are not involved in the antinociception observed at the 4th hour after Cg injection.Conclusion: These data support the hypothesis that neutrophils and the calcium-binding protein MRP-14 are participants of the endogenous control of inflammatory pain in mice despite the model of acute inflammation used.

Sign in / Sign up

Export Citation Format

Share Document