S100A10, annexin A2, and annexin a2 heterotetramer as candidate plasminogen receptors

Kwon, Mijung; MacLeod, Travis J.; Zhang, Yi; Waisman, David M.

doi:10.2741/1529

Cited by 159 publications

(174 citation statements)

References 222 publications

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“…The cell surface S100A10/annexin II complex activates plasminogen to form plasmin. (8) The loss of S100A10 from the extracellular surface of cancer cells results in a significant loss in plasmin generation. (8) Furthermore, S100A10 knock-down cells exhibit a dramatic loss in extracellular matrix degradation and invasiveness as well as reduced metastasis.…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of S100A10, annexin II and B‐FABP expression as markers for renal cell carcinoma

et al. 2006

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This study aimed to analyze expression of S100A10, annexin II and B-FABP genes in renal cell carcinoma (RCC) and their potential value as tumor markers. Furthermore, any correlation between the gene expression and prognostic indicators of RCC was analyzed. Expression of each gene was estimated by RT-PCR in the nonneoplastic (normal) and tumorous parts of resected kidney samples. Also, each antigen was immunostained in RCC and normal kidney tissues. Expression of the S100A10 gene averaged 2.5-fold higher in the tumor than that in the normal tissues (n = 47), after standardization against that of β β β β-actin. However, expression of annexin II, a natural ligand of S100A10, was only 1.64-fold higher. In the tissue sections of RCC, S100A10 and annexin II were immunostained in membranes. In the normal renal epithelia, however, both antigens were stained in the Bowman's capsule and the tubules from Henle's loop through the collecting duct system, but not in the proximal tubules, from where most RCC are derived. In contrast, expression of the B-FABP gene was 20-fold higher in the tumor. No B-FABP was immunohistochemically detected in normal kidney sections, but it was stained in the cytoplasm of RCC tissue sections. S100A10 and B-FABP genes were overexpressed regardless of nuclear grade and stage of RCC. Immunopositivity in RCC tissues (n = 13) was 100% for S100A10 and annexin II, and 70% for B-FABP; however, no clear relationship was observed in either antigen with nuclear grade and stage. It was found that all three performed well as RCC markers. B-FABP was most specific to RCC, as it was expressed little in normal kidney tissues. (Cancer Sci 2007; 98: 77-82) W e have previously described the overexpression of S100A10 in renal cell carcinoma (RCC) cells compared with the normal human kidney cDNA library.(1) Such overexpression has been confirmed in RCC and non-neoplastic (normal) tissues in surgically resected kidneys (n = 7).(1,2) S100A10 is a member of the S100 family of proteins that are small acidic calcium-binding proteins with two helix-loop-helix EF-hand motifs. Twenty human S100 family members are expressed in a cell-and tissue-specific manner, and are responsible for a variety of cellular processes including cell proliferation and differentiation.(3,4) Sixteen of their genes (designated S100A1-S100A16) are clustered on the chromosome 1q21 region, where a number of chromosomal abnormalities occur with neoplasias.(4) S100A10 forms a heterotetramer with annexin II (S100A10) 2 (annexin II) 2 , and the complex localizes in the extracellular membrane of various cancer cells. In the present study, we estimated the gene expression of S100A10 and annexin II by reverse transcription-polymerase chain reaction (RT-PCR) in a larger number of surgically resected RCC samples (n = 47) after standardization for the expression of β-actin in each sample. Then we immunohistochemically investigated the expression of S100A10 and annexin II in RCC and normal kidney tissues (n = 13). The extracellular S100A10/ annexin II complex f...

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Section: Discussionmentioning

confidence: 99%

“…These processes are thought to be correlated with tumor invasiveness, metastasis and angiogenesis. (8) Therefore, we examined any correlation between expression of S100A10 and annexin II and prognostic predicators of RCC. As prognostic markers, we chose nuclear grade and stage.…”

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Evaluation of S100A10, annexin II and B‐FABP expression as markers for renal cell carcinoma

et al. 2006

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“…Complex formation with p11 increases the affinity of A2 for calcium and phospholipids, thereby directing it to cellular membranes (4). Components of the (A2⅐p11) 2 tetramer, moreover, specifically bind tissue plasminogen activator (t-PA) and plasminogen and strongly enhance plasmin generation (5)(6)(7)(8)52).…”

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confidence: 99%

Feedback Regulation of Endothelial Cell Surface Plasmin Generation by PKC-dependent Phosphorylation of Annexin A2

He¹,

Sui

Xiong

et al. 2011

Journal of Biological Chemistry

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In response to blood vessel injury, hemostasis is initiated by platelet activation, advanced by thrombin generation, and tempered by fibrinolysis. The primary fibrinolytic protease, plasmin, can be activated either on a fibrin-containing thrombus or on cells. Annexin A2 (A2) heterotetramer (A2⅐p11) 2 is a key profibrinolytic complex that assembles plasminogen and tissue plasminogen activator and promotes plasmin generation. We now report that, in endothelial cells, plasmin specifically induces activation of conventional PKC, which phosphorylates serine 11 and serine 25 of A2, triggering dissociation of the (A2⅐p11) 2 tetramer. The resulting free p11 undergoes ubiquitinmediated proteasomal degradation, thus preventing further translocation of A2 to the cell surface. In vivo, pretreatment of A2 ؉/؉ but not A2 ؊/؊ mice with a conventional PKC inhibitor significantly reduced thrombosis in a carotid artery injury model. These results indicate that augmentation of fibrinolytic vascular surveillance by blockade of serine phosphorylation is A2-dependent. We also demonstrate that plasmin-induced phosphorylation of A2 requires both cleavage of A2 and activation of Toll-like receptor 4 on the cell surface. We propose that plasmin can limit its own generation by triggering a finely tuned "feedback" mechanism whereby A2 becomes serine-phosphorylated, dissociates from p11, and fails to translocate to the cell surface.The human hemostatic system represents a coordinated balance between procoagulant and anticoagulant/profibrinolytic activities. Together, these systems prevent blood loss while maintaining blood flow. Plasmin, the major protease of the fibrinolytic system, acts to digest insoluble fibrin into soluble fibrin degradation products. Plasmin generation is modulated by plasminogen activators and plasminogen activator inhibitors and is further regulated by binding of plasminogen and its activators to cell surface receptors (1). Membrane-associated annexin A2 (A2) 3 is part of a heterotetrameric complex in which the N termini of two copies of A2 bind to two copies of the S100 family protein, S100A10 (p11) (2). A2, a member of the annexin superfamily, consists of a highly conserved C-terminal phospholipid-binding core domain and an N-terminal ligandinteracting domain (3). Complex formation with p11 increases the affinity of A2 for calcium and phospholipids, thereby directing it to cellular membranes (4). Components of the (A2⅐p11) 2 tetramer, moreover, specifically bind tissue plasminogen activator (t-PA) and plasminogen and strongly enhance plasmin generation (5-8, 52).Several lines of evidence identify the (A2⅐p11) 2 complex as a significant regulator of fibrin balance in vivo. First, A2 Ϫ/Ϫ microvascular endothelial cells lack t-PA cofactor activity, and the fibrin content of highly perfused A2 Ϫ/Ϫ tissues is ϳ2-fold greater than that observed in wild type controls (9). In addition, arterial injury in A2 Ϫ/Ϫ mice is followed by a 2-fold increase in thrombotic vascular occlusion with an equivalent reduction in blood flo...

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“…21,30,31 Several binding partners of DLC1 have been identified, including members of the tensin family of focal adhesion proteins (eg, tensin1, tensin2, and C-terminal tensin like (cten)), p120RasGAP, elongation factor 1A1 (EF1A1), and S100A10, which further delineates its mechanism and its role in inhibiting cancer cell migration, proliferation, and metastasis. 30,[32][33][34][35] DLC1 gene silencing promotes pro-angiogenic responses through upregulation of vascular endothelial growth factor, accompanied by the accumulation of hypoxia-inducible factor 1 alpha and its nuclear localization. 36 Since its discovery, compelling evidence has accumulated that demonstrates a role for DLC1 as a bonafide tumor suppressor gene in different types of human cancers.…”

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Loss of DLC1 is an independent prognostic factor in patients with oral squamous cell carcinoma

et al. 2012

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Deleted in liver cancer (DLC1), a Rho GTPase-activating protein, was observed to be differentially expressed in oral squamous cell carcinoma in comparison with normal tissues using tissue proteomics. In the current study, we investigated the clinical significance of loss of DLC1 expression in different stages of development of oral squamous cell carcinoma to determine its potential as a biomarker for oral dysplasia and prognosis of oral squamous cell carcinoma. Immunohistochemical analysis of DLC1 expression was carried out in oral squamous cell carcinoma patients (n ¼ 214), dysplasia (n ¼ 51), hyperplastic squamous mucosa (n ¼ 45), and histologically normal oral tissues (n ¼ 80), and correlated with clinicopathological parameters and disease prognosis over 91 months for oral squamous cell carcinomas. Loss of DLC1 expression was observed in oral squamous cell carcinoma (64%), oral dysplasia (31%), hyperplastic squamous mucosa (22%), and normal mucosa (16%). Significant loss of DLC1 expression was observed in oral squamous cell carcinomas as compared with dysplasia (Po0.001, odds ratio ¼ 3.8, 95% CI ¼ 2.0-7.3), suggesting it may be an important event involved in cancer progression. Among oral squamous cell carcinomas, the loss of DLC1 expression was significantly associated with poor prognosis (P ¼ 0.021, hazards ratio (HR) ¼ 1.8, 95% CI ¼ 1.1-2.9). Multivariate analysis revealed loss of DLC1 (P ¼ 0.023, HR ¼ 2.1, 95% CI ¼ 1.2-3.9) and histopathological grade (P ¼ 0.015, HR ¼ 1.7, 95% CI ¼ 1.1-2.7) to be independent predictors for disease-free survival in oral squamous cell carcinoma patients in comparison with known prognostic factors, viz. tumor stage, nodal status, and overall stage. Loss of DLC1 expression emerged as an important biomarker for predicting patients diagnosed with oral dysplasia at high risk of transformation upon future validation in longitudinal studies. Loss of DLC1 expression is a poor prognostic marker for oral squamous cell carcinoma patients.

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S100A10, annexin A2, and annexin a2 heterotetramer as candidate plasminogen receptors

Cited by 159 publications

References 222 publications

Evaluation of S100A10, annexin II and B‐FABP expression as markers for renal cell carcinoma

Evaluation of S100A10, annexin II and B‐FABP expression as markers for renal cell carcinoma

Feedback Regulation of Endothelial Cell Surface Plasmin Generation by PKC-dependent Phosphorylation of Annexin A2

Loss of DLC1 is an independent prognostic factor in patients with oral squamous cell carcinoma

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