Rac regulates collagen-induced HSP27 phosphorylation via p44/p42 MAP kinase in human platelets

Kageyama, Yasunari; Doi, Tomoaki; Akamatsu, Shigeru; Kuroyanagi, Gen; Kondo, Akira; Mizutani, Jun; Otsuka, Takanobu; Tokuda, Harukuni; Kozawa, Osamu; Ogura, Shinji

doi:10.3892/ijmm.2013.1455

Cited by 16 publications

(29 citation statements)

References 24 publications

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“…Regarding HSP27 in human platelets, we have reported that ADP-or collagen-induced HSP27 phosphorylation is mediated through p44/p42 mitogen-activated protein kinase (MAPK), and HSP27 phosphorylation is accompanied with both the secretion of PDGF-AB and the release of sCD40L [28,29]. In addition, we showed that Rac positively regulates collagen-induced HSP27 phosphorylation via p44/p42 MAPK [30]. Moreover, in our recent studies [31,32], we demonstrated that phosphorylated-HSP27 is released from platelets stimulated by collagen or TRAP in diabetic patients.…”

Section: Introductionmentioning

confidence: 85%

“…Regarding HSP27 phosphorylation in human platelets, we previously showed that Rac postitively regulates collagen-induced HSP27 phosphorylation at a point upstream of p44/ p42 MAPK [30]. In addition, we demonstrated that the TRAP-stimulated activation of Akt is involved in the phosphorylation of HSP27 and its subsequent release in diabetic patients [32].…”

Section: Effects Of Trap On the Phosphorylation Of P38 Mapk P44/p42 mentioning

confidence: 91%

“…We have previously shown that Rac positively regulates collagen-induced human platelet activation via p44/p42 MAPK [30]. Thus, we investigated whether PAR activation could induce the activation of these intracellular molecules in human platelets.…”

Section: Discussionmentioning

confidence: 99%

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Rac Regulates the TRAP-Induced Release of Phosphorylated-HSP27 from Human Platelets via p38 MAP Kinase but Not JNK

Uematsu

Enomoto

Onuma

et al. 2018

Cell Physiol Biochem

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Background/Aims: Thrombin induces the activation of human platelets through protease-activated receptor (PAR) 1 and PAR4, and Rac, a member of the Rho family of small GTPases, is implicated in PAR activation. We previously reported that phosphorylated-heat shock protein 27 (HSP27) is released from the thrombin receptor-activating peptide (TRAP)-stimulated platelets of diabetic patients. In the present study, we investigated the role of Rac in the TRAP-elicited release of phosphorylated-HSP27 from human platelets. Methods: Platelet aggregation was measured using an aggregometer with laser scattering. Protein phosphorylation was analyzed by Western blotting. The levels of phosphorylated-HSP27 and platelet-derived growth factor-AB (PDGF-AB) were measured by enzyme-linked immunosorbent assays. Results: NSC23766, an inhibitor of Rac-guanine nucleotide exchange factor interaction, suppressed the TRAP-elicited release of phosphorylated-HSP27 as well as platelet aggregation. The TRAP-induced phosphorylation of HSP27, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) was attenuated by NSC23766. SB203580, a p38 MAPK inhibitor, but not SP600125, a JNK inhibitor, suppressed the release of phosphorylated-HSP27 in addition to HSP27 phosphorylation. On the other hand, both SB203580 and SP600125 reduced the TRAP-stimulated secretion of PDGF-AB. Conclusion: Our results strongly suggest that Rac acts as a positive regulator of the PAR-elicited release of phosphorylated-HSP27 from human platelets via p38 MAPK but not JNK.

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Section: Introductionmentioning

confidence: 85%

Section: Effects Of Trap On the Phosphorylation Of P38 Mapk P44/p42 mentioning

confidence: 91%

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Rac Regulates the TRAP-Induced Release of Phosphorylated-HSP27 from Human Platelets via p38 MAP Kinase but Not JNK

Uematsu

Enomoto

Onuma

et al. 2018

Cell Physiol Biochem

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“…In response to collagen, it has been reported that p38 MAP kinase is activated and regulates HSP27 phosphorylation in the process of human platelet activation [ 18 ]. We have recently reported that Rac, a low-molecular weight GTP-binding protein, regulates collagen-induced HSP27 phosphorylation via p44/p42 MAP kinase in human platelets, leading to the secretion of PDGF-AB [ 19 ]. However, the clinical relevance of HSP27 phosphorylation in human platelets has not yet been precisely clarified.…”

Section: Introductionmentioning

confidence: 99%

Release of Phosphorylated HSP27 (HSPB1) from Platelets Is Accompanied with the Acceleration of Aggregation in Diabetic Patients

et al. 2015

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We investigated the relationship between HSP27 phosphorylation and collagen-stimulated activation of platelets in patients with diabetes mellitus (DM). Platelet-rich plasma was prepared from blood of type 2 DM patients. The platelet aggregation was analyzed in size of aggregates by an aggregometer using a laser scattering method. The protein phosphorylation was analyzed by Western blotting. Phosphorylated-HSP27 and PDGF-AB released from platelets were measured by ELISA. The phosphorylated-HSP27 levels at Ser-78 and Ser-82 induced by collagen were directly proportional to the platelet aggregation. Total HSP27 levels in platelets were decreased concomitantly with the phosphorylation. The released HSP27 levels were significantly correlated with the phosphorylated levels of HSP27 in the platelets stimulated by 0.3 μg/ml collagen. The low dose collagen-stimulated release of HSP27 was detected but relatively small in healthy donors. The released levels of PDGF-AB were in parallel with the levels of released HSP27. Area under the curve (AUC) of small aggregation (9-25 μm) induced by 0.3 μg/ml collagen was inversely proportional to the levels of released HSP27. AUC of large aggregation (50-70 μm) was directly proportional to the levels of released HSP27. Exogenous recombinant phosphorylated- HSP27 hardly affected the aggregation or the released levels of PDGF-AB induced by collagen. These results strongly suggest that HSP27 is released from human platelets accompanied with its phosphorylation induced by collagen, which is correlated with the acceleration of platelet aggregation in type 2 DM patients.

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“…It is well known that the members of MAP kinase superfamily such as p38 MAP kinase are involved in the phosphorylation of HSP27 in the process of human platelet activation (13,19). We previously reported that Rac, a low-molecular weight GTP-binding protein, regulates HSP27 phosphorylation stimulated by collagen via p44/p42 MAP kinase in human platelets (20). Furthermore, we have recently shown that phosphorylated-HSP27 stimulated by collagen or thrombin receptor-activating protein (TRAP) in the platelets of type 2 DM patients is released together with the secretion of PDGF-AB (21,22).…”

Section: Ristocetin Induces Phosphorylated-hsp27 (Hspb1)mentioning

confidence: 99%

Ristocetin induces phosphorylated‑HSP27 (HSPB1) release from the platelets of type 2 DM patients: Anti‑platelet agent‑effect on the release

et al. 2018

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Abstract. It has been previously reported that HSP27 is released from platelets in type 2 diabetes mellitus (DM) patients according to phosphorylation. In the present study, we investigated the effect of ristocetin, a glycoprotein (GP) Ib/IX/V activator, on the release of HSP27 and the effect of anti-platelet agents, such as acetylsalicylic acid (ASA), on this release. Forty-six patients with type 2 DM were recruited, and classified into two groups depending on administration of anti-platelet agents, resulting in 31 patients without these agents (control group) and 15 patients with them (anti-platelet group). Ristocetin potently induced the aggregation of platelets in the two groups. Ristocetin-induced changes of the area under the curve of light transmittance and the ratio of the size of platelet aggregates in the anti-platelet group were slightly different from those in the control group. On the other hand, the levels of phosphorylated-HSP27 induced by ristocetin in the platelets from a patient of the anti-platelet group taking ASA were significantly lower than those from a patient of the control group. The levels of HSP27 release from the ristocetin-stimulated platelets were significantly correlated with the levels of phosphorylated-HSP27 in the platelets from patients in the two groups. The levels of HSP27 release and those of platelet-derived growth factor-AB (PDGF-AB) secretion stimulated by ristocetin in the anti-platelet group were lower than those in the control group. In addition, the levels of HSP27 release and those of PDGF-AB secretion stimulated by ADP in the anti-platelet group were lower than those in the control group. These results strongly suggest that anti-platelet agents inhibit the HSP27 release from platelets stimulated by ristocetin but not the aggregation in type 2 DM patients.

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Rac regulates collagen-induced HSP27 phosphorylation via p44/p42 MAP kinase in human platelets

Cited by 16 publications

References 24 publications

Rac Regulates the TRAP-Induced Release of Phosphorylated-HSP27 from Human Platelets via p38 MAP Kinase but Not JNK

Rac Regulates the TRAP-Induced Release of Phosphorylated-HSP27 from Human Platelets via p38 MAP Kinase but Not JNK

Release of Phosphorylated HSP27 (HSPB1) from Platelets Is Accompanied with the Acceleration of Aggregation in Diabetic Patients

Ristocetin induces phosphorylated‑HSP27 (HSPB1) release from the platelets of type 2 DM patients: Anti‑platelet agent‑effect on the release

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