Protein phosphorylation and its role in the regulation of Annexin A2 function

Grindheim, Ann Kari; Saraste, Jaakko; Vedeler, Anni

doi:10.1016/j.bbagen.2017.08.024

Cited by 101 publications

(143 citation statements)

References 219 publications

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“…Although our results suggest that EPAC1 acts via PLCε‐PKC to regulate AnxA2 S25 phosphorylation, they do not rule out of the involvement of S11, which is a known in vitro PKC phosphorylation site (9). In addition, it has been suggested that phosphorylation of S25 by PKC may lead to the exposure of S11 and subsequent phosphorylation by another kinase, such as PKA or calmodulin kinase (35, 38). Considering that EPAC1 has been reported to activate calmodulin kinase via PLCε‐PKCε (39), it is also possible that EPAC1 regulates AnxA2 function by sequential phosphorylation of S25 and S11, mediated by PKC and calmodulin kinase, respectively.…”

Section: Discussionmentioning

confidence: 99%

EPAC1 regulates endothelial annexin A2 cell surface translocation and plasminogen activation

Mei

Cheng

2018

FASEB j.

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Annexins, a family of highly conserved calcium- and phospholipid-binding proteins, play important roles in a wide range of physiologic functions. Among the 12 known annexins in humans, annexin A2 (AnxA2) is one of the most extensively studied and has been implicated in various human diseases. AnxA2 can exist as a monomer or a heterotetrameric complex with S100A10 (P11) and plays a critical role in many cellular processes, including exocytosis, endocytosis, and membrane organization. At the endothelial cell surface, the (AnxA2⋅P11) tetramer-acting as a coreceptor for plasminogen and tissue plasminogen activator (tPA)-accelerates tPA-dependent activation of the fibrinolytic protease, plasmin, the enzyme that is responsible for thrombus dissolution and the degradation of fibrin. This study demonstrates that EPAC1 (exchange proteins directly activated by cAMP isoform 1) interacts with AnxA2 and regulates its biologic functions by modulating its membrane translocation in endothelial cells. By using genetic and pharmacologic approaches, we demonstrate that EPAC1-acting via the PLCε-PKC pathway-inhibits AnxA2 surface translocation and plasminogen activation. These results suggest that EPAC1 plays a role in the regulation of fibrinolysis in endothelial cells and may represent a novel therapeutic target for disorders of fibrinolysis.-Yang, W., Mei, F. C., Cheng, X. EPAC1 regulates endothelial annexin A2 cell surface translocation and plasminogen activation.

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Section: Discussionmentioning

confidence: 99%

EPAC1 regulates endothelial annexin A2 cell surface translocation and plasminogen activation

Mei

Cheng

2018

FASEB j.

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“…Recent studies have revealed several key molecules involved in the development of drug resistance and associated signal pathways responsible for cancer progression [2,12]. One molecule is Annexin A2 (Anxa2), a calcium-dependent phospholipid-binding protein [2,[12][13][14]. Anxa2 has been shown as a multifunctional protein implicated in many biological processes [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

“…One molecule is Annexin A2 (Anxa2), a calcium-dependent phospholipid-binding protein [2,[12][13][14]. Anxa2 has been shown as a multifunctional protein implicated in many biological processes [13][14][15]. Its abnormal expression is associated with a variety of diseases, especially cancer [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

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Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells

Fan

et al. 2019

Breast Cancer Res

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Background: Acquirement of resistance is always associated with a highly aggressive phenotype of tumor cells. Recent studies have revealed that Annexin A2 (Anxa2) is a key protein that links drug resistance and cancer metastasis. A high level of Anxa2 in cancer tissues is correlated to a highly aggressive phenotype. Increased Anxa2 expression appears to be specific in many drug-resistant cancer cells. The functional activity of Anxa2 is regulated by tyrosine phosphorylation at the Tyr23 site. Nevertheless, the accurate molecular mechanisms underlying the regulation of Anxa2 tyrosine phosphorylation and whether phosphorylation is necessary for the enhanced invasive phenotype of drug-resistant cells remain unknown. Methods: Small interfering RNAs, small molecule inhibitors, overexpression, loss of function or gain of function, rescue experiments, Western blot, wound healing assays, transwell assays, and in vivo metastasis mice models were used to investigate the functional effects of Rack1 and Src on the tyrosine phosphorylation of Anxa2 and the invasion and metastatic potential of drug-resistant breast cancer cells. The interaction among Rack1, Src, and Anxa2 in drug-resistant cells was verified by co-immunoprecipitation assay. Results: We demonstrated that Anxa2 Tyr23 phosphorylation is necessary for multidrug-resistant breast cancer invasion and metastasis. Rack1 is required for the invasive and metastatic potential of drug-resistant breast cancer cells through modulating Anxa2 phosphorylation. We provided evidence that Rack1 acts as a signal hub and mediates the interaction between Src and Anxa2, thereby facilitating Anxa2 phosphorylation by Src kinase. Conclusions: Our findings suggest a convergence point role of Rack1/Src/Anxa2 complex in the crosstalk between drug resistance and cancer aggressiveness. The interaction between Anxa2 and Rack1/Src is responsible for the association between drug resistance and invasive/metastatic potential in breast cancer cells. Thus, our findings provide novel insights on the mechanism underlying the functional linkage between drug resistance and cancer aggressiveness.

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“…Annexin A2 can be phosphorylated in residue Tyr23, and it is also phosphorylated by PKC on serine residues in a calcium and phospholipid dependent manner (Johnsson et al 1986;Khanna et al 1986) (for review (Grindheim et al 2017)). Tyrosine phosphorylation of AnxA2 has been involved in the regulation of cofilin-dependent actin cytoskeletal dynamics (Graauw et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Annexin A2 expression and partners during epithelial cell differentiation

Zibouche

Illien

Ayala-Sanmartín

2019

Biochem. Cell Biol.

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The members of the annexin family of calcium-and phospholipid-binding proteins participate in different cellular processes. Annexin A2 binds to S100A10 forming a functional heterotetrameric protein that has been involved in many cellular functions such as exocytosis, endocytosis, cell junction formation and actin cytoskeleton dynamics. Herein, we studied annexin A2 cellular movements and looked for its partners during epithelial cell differentiation. By using immunofluorescence, mass spectrometry and western blot analyses after S100A10 affinity column separation, we identified several annexin A2-S100A10 partner candidates. The association of putative annexin A2-S100A10 partner candidates obtained by MS after column affinity was validated by immunofluorescence and sucrose density gradient separation. The results show that three proteins were clearly associated to AnxA2: E-cadherin, actin and caveolin 1. Overall the data show that annexin A2 is able to associate to molecular complexes containing actin, caveolin 1 and flotillin 2 before epithelial differentiation and to complexes containing E-Cadherin, actin and caveolin 1, but not flotillin 2 after cell differentiation. The results indicate that actin, caveolin 1 and E-cadherin are the principal 2 protein partners of annexin A2 in epithelial cells and that the serine phosphorylation of the Nterminal domain does not play an essential role during epithelial cell differentiation.

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Protein phosphorylation and its role in the regulation of Annexin A2 function

Cited by 101 publications

References 219 publications

EPAC1 regulates endothelial annexin A2 cell surface translocation and plasminogen activation

EPAC1 regulates endothelial annexin A2 cell surface translocation and plasminogen activation

Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells

Annexin A2 expression and partners during epithelial cell differentiation

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