Reactive oxygen species exert opposite effects on Tyr23 phosphorylation of the nuclear and cortical pools of Annexin A2

Grindheim, Ann Kari; Hollås, Hanne; Raddum, Aase M.; Saraste, Jaakko; Vedeler, Anni

doi:10.1242/jcs.173195

Cited by 21 publications

(24 citation statements)

References 116 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…), showing that its subcellular distribution differs from that of pSer25AnxA2. Thus, the two phosphorylated forms of AnxA2 are most likely functionally distinct . Moreover, these data are in agreement with the finding that the two phosphorylation events at Ser25 and Tyr23 of AnxA2 are mutually exclusive .…”

Section: Resultssupporting

confidence: 90%

“…For example, the functions of the PML protein are regulated by phosphorylation, ubiquitination and sumoylation either in combinations or alone (discussed in ). We previously observed that pTyr23AnxA2 is also ubiquitinated , although the pattern of its high‐molecular‐mass forms differs from that of the pSer25AnxA2 (Fig. ) .…”

Section: Resultsmentioning

confidence: 84%

“…We previously observed that pTyr23AnxA2 is also ubiquitinated [41], although the pattern of its high-molecular-mass forms differs from that of the pSer25AnxA2 (Fig. 6) [41]. Furthermore, the two phosphorylated forms of the protein are localised to distinct cellular compartments ( Fig.…”

Section: Pser25anxa2 Associates With Perinuclear Nonpolysomal Mrnp Comentioning

confidence: 84%

See 2 more Smart Citations

Post‐translational modifications of Annexin A2 are linked to its association with perinuclear nonpolysomal mRNP complexes

et al. 2017

Self Cite

View full text Add to dashboard Cite

Various post‐translational modifications (PTMs) regulate the localisation and function of the multifunctional protein Annexin A2 (AnxA2). In addition to its various tasks as a cytoskeletal‐ and membrane‐associated protein, AnxA2 can function as a trans ‐acting protein binding to cis ‐acting sequences of specific mRNAs. In the present study, we have examined the role of Ser25 phosphorylation in subcellular localisation of AnxA2 and its interaction with mRNP complexes. Subcellular fractionation and confocal microscopy of rat neuroendocrine PC12 cells showed that Ser25‐phosphorylated AnxA2 (pSer25AnxA2) is absent from the nucleus and mainly localised to the perinuclear region, evidently associating with both membranes and cytoskeletal elements. Perinuclear targeting of AnxA2 was abolished by inhibition of protein kinase C activity, which resulted in cortical enrichment of the protein. Although oligo(dT)‐affinity purification of mRNAs revealed that pSer25AnxA2 associates with nonpolysomal, translationally inactive mRNP complexes, it displayed only partial overlap with a marker of P‐bodies. The phosphorylated protein is present as high‐molecular‐mass forms, indicating that it contains additional covalent PTMs, apparently triggered by its Ser25 phosphorylation. The subcellular distributions of these forms clearly differ from the main form of AnxA2 and are also distinct from that of Tyr23‐phosphorylated AnxA2. Immunoprecipitation verified that these high‐molecular‐mass forms are due to ubiquitination and/or sumoylation. Moreover, these results indicate that Ser25 phosphorylation and ubiquitin/SUMO1 conjugation of AnxA2 promote its association with nonpolysomal mRNAs, providing evidence of a possible mechanism to sequester a subpopulation of mRNAs in a translationally inactive and transport competent form at a distinct subcellular localisation.

show abstract

Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 84%

See 1 more Smart Citation

Post‐translational modifications of Annexin A2 are linked to its association with perinuclear nonpolysomal mRNP complexes

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Our recent results indicate that different subcellular responses may occur simultaneously. 12 Thus, when cells are exposed to oxidative stress, AnxA2 in the nucleus is dephosphorylated on Tyr23, while cortical AnxA2 is phosphorylated on the same residue by the Src kinase. 12 AnxA2 itself may in turn act both as a regulator and effector of the Src kinase, at least in the case of v-Src.…”

Section: Introductionmentioning

confidence: 99%

“… 12 Thus, when cells are exposed to oxidative stress, AnxA2 in the nucleus is dephosphorylated on Tyr23, while cortical AnxA2 is phosphorylated on the same residue by the Src kinase. 12 AnxA2 itself may in turn act both as a regulator and effector of the Src kinase, at least in the case of v-Src. 13 Tyr23 phosphorylation of AnxA2 leads to its binding to the cytoplasmic surface of endosomes, 14 which subsequently develop into multivesicular bodies (MVBs), 15 due to the invagination of the endosomal membrane.…”

Section: Introductionmentioning

confidence: 99%

Extracellular vesicles released from cells exposed to reactive oxygen species increase annexin A2 expression and survival of target cells exposed to the same conditions

Grindheim

Vedeler

2016

Communicative & Integrative Biology

Self Cite

View full text Add to dashboard Cite

Annexin A2 (AnxA2) is present in multiple cellular compartments and interacts with numerous ligands including calcium, proteins, cholesterol, negatively charged phospholipids and RNA. These interactions are tightly regulated by its post-translational modifications. The levels of AnxA2 and its Tyr23 phosphorylated form (pTyr23AnxA2) are increased in many cancers and the protein is involved in malignant cell transformation, metastasis and angiogenesis. Our previous studies of rat pheochromocytoma (PC12) cells showed that reactive oxygen species (ROS) induce rapid, simultaneous and transient dephosphorylation of nuclear AnxA2, most likely associating with PML bodies, while AnxA2 associated with F-actin at the cell cortex undergoes Tyr23 phosphorylation. The pTyr23AnxA2 in the periphery of the cells is incorporated into intraluminal vesicles of multivesicular endosomes and subsequently released to the extracellular space. We show here that extracellular vesicles (EVs) from cells exposed to ROS prime untreated PC12 cells to better tolerate subsequent oxidative stress, thus enhancing their survival. There is an increase in the levels of pTyr23AnxA2 and AnxA2 in the primed cells, suggesting that AnxA2 is involved in their survival. This increase is due to an upregulation of AnxA2 expression both at the transcriptional and translational levels after relatively short term (2 h) exposure to primed EVs.

show abstract

Proline/serine‐rich coiled‐coil protein 1 inhibits macrophage inflammation and delays atherosclerotic progression by binding to Annexin A2

Pan

Guo

et al. 2023

Clinical & Translational Med

View full text Add to dashboard Cite

Background Atherosclerosis (AS), the main pathological basis of life‐threatening cardiovascular disease, is essentially caused by chronic macrophage inflammation. Overexpression of proline/serine‐rich coiled‐coil protein 1 (PSRC1) reduces macrophage inflammatory responses and delays AS development. However, the exact mechanism of PSRC1 is unclear. Methods Proteins interacting with PSRC1 were screened by proteomics in RAW264.7 cells, followed by RT‒qPCR, immunoprecipitation and immunofluorescence to explore the specific mechanistic pathways affecting inflammation. CRISPR‒Cas9 constructs for PSRC1−/−ApoE−/−(DKO) mice and high‐fat diet‐fed ApoE−/− and DKO mice were used for AS models for in vivo experiments. Upstream transcription factors of PSRC1 were predicted by ATAC‐seq, ChIP‐seq and UCSC, and the regulatory mechanism was verified by ChIP‒qPCR and dual luciferase assays. Peripheral blood serum and monocytes were collected from coronary artery disease (CAD) patients and non‐CAD patients. Results Increased binding of ANXA2 to PSRC1 in macrophages under oxidized low‐density lipoprotein stimulation and decreased release of ANXA2 to the extracellular compartment were observed. Knockdown of ANXA2 in AS model mice delayed AS progression. Knockdown of ANXA2 in DKO mice reversed the AS‐promoting effect of PSRC1 knockdown. Mechanistically, ANXA2 promotes STAT3 phosphorylation, which in turn promotes inflammatory responses. In addition, SP1 is a PSRC1 upstream repressive transcription factor, and the SP1 inhibitor mithramycin (Mith) elevated PSRC1 expression and exerted anti‐AS effects in AS model mice. Patients with CAD had considerably greater serum levels of ANXA2 than those without CAD, and Mith reduced the secretion of ANXA2 in peripheral blood monocytes of CAD patients. Conclusion In macrophages, PSRC1 can interact with ANXA2 to inhibit its extracellular release and delay AS development. SP1 is an upstream transcription factor of PSRC1 and inhibits the transcription of PSRC1. The SP1 inhibitor Mith can elevate PSRC1 levels and slow AS progression while reducing ANXA2 release from monocytes in CAD patients. Mith is expected to be a new agent for AS treatment.

show abstract

Reactive oxygen species exert opposite effects on Tyr23 phosphorylation of the nuclear and cortical pools of Annexin A2

Cited by 21 publications

References 116 publications

Post‐translational modifications of Annexin A2 are linked to its association with perinuclear nonpolysomal mRNP complexes

Post‐translational modifications of Annexin A2 are linked to its association with perinuclear nonpolysomal mRNP complexes

Extracellular vesicles released from cells exposed to reactive oxygen species increase annexin A2 expression and survival of target cells exposed to the same conditions

Proline/serine‐rich coiled‐coil protein 1 inhibits macrophage inflammation and delays atherosclerotic progression by binding to Annexin A2

Contact Info

Product

Resources

About