LIM kinase-1 selectively promotes glycoprotein Ib-IX–mediated TXA2 synthesis, platelet activation, and thrombosis

Estevez, Brian; Stojanovic‐Terpo, Aleksandra; Delaney, Michael Keegan; O’Brien, Kelly; Berndt, Michael C.; Ruan, Changgeng; Du, Xiaoping

doi:10.1182/blood-2012-12-470765

Cited by 36 publications

(25 citation statements)

References 41 publications

(64 reference statements)

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“…We next evaluated proplatelet formation on a fibrinogen matrix. For WT MKs, the percentage of proplatelet-forming MKs was similar in LIMKi-and vehicle-treated (DMSO) cells ( Figure 6C), which is compatible with the normal platelet count reported in LIMK-deficient mice (26). Interestingly, while the percentage of 2B MKs that formed proplatelets remained low in the presence of vehicle (18% ± 1%), treatment of 2B MKs with LIMKi restored proplatelet formation to a level similar to that of vehicle-treated WT MKs (43% ± 2% and 52% ± 10% in LIMKi-treated 2B MKs and vehicle-treated WT MKs, respectively; P > 0.05; Figure 6C).…”

Section: B and D-g)supporting

confidence: 87%

“…Two aspects are of relevance in this regard. First, it has been reported that artificial, ristocetin-stimulated complex formation between vWF and GPIbα induces activation of the LIMK/cofilin pathway (26). We therefore considered the possibility that outside-in signaling induced upon complex formation by freshly secreted vWF/p.V1316M and cell-surface-exposed GPIbα could be responsible for the activation of the LIMK/ cofilin pathway.…”

Section: V1316m (2b) Megakaryocytes (Mks)mentioning

confidence: 99%

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LIM kinase/cofilin dysregulation promotes macrothrombocytopenia in severe von Willebrand disease-type 2B

et al. 2016

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Section: B and D-g)supporting

confidence: 87%

Section: V1316m (2b) Megakaryocytes (Mks)mentioning

confidence: 99%

LIM kinase/cofilin dysregulation promotes macrothrombocytopenia in severe von Willebrand disease-type 2B

et al. 2016

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“…Accordingly, PAK may regulate platelet actin dynamics through the LIMK1-mediated phosphorylation of cofilin. Intriguingly, LIMK1 also contributes to platelet function through glycoprotein Ib-IXmediated TxA2 synthesis; however, the roles of PAK phosphorylation actin-independent processes such as platelet TxA2 synthesis remain to be examined (16,36,37). Together with data demonstrating a role for PAK in thrombin-mediated platelet activation, these findings connect platelet Rho GTPase signaling to a system of PAK effectors with central roles in platelet physiological functions, including lamellipodia formation, aggregation, and calcium-mediated phosphatidylserine exposure.…”

Section: Discussionmentioning

confidence: 86%

The PAK system links Rho GTPase signaling to thrombin-mediated platelet activation

Aslan

Baker

Loren

et al. 2013

American Journal of Physiology-Cell Physiology

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Regulation of the platelet actin cytoskeleton by the Rho family of small GTPases is essential for the proper maintenance of hemostasis. However, little is known about how intracellular platelet activation from Rho GTPase family members, including Rac, Cdc42, and Rho, translate into changes in platelet actin structures. To better understand how Rho family GTPases coordinate platelet activation, we identified platelet proteins associated with Rac1, a Rho GTPase family member, and actin regulatory protein essential for platelet hemostatic function. Mass spectrometry analysis revealed that upon platelet activation with thrombin, Rac1 associates with a set of effectors of the p21-activated kinases (PAKs), including GIT1, βPIX, and guanine nucleotide exchange factor GEFH1. Platelet activation by thrombin triggered the PAK-dependent phosphorylation of GIT1, GEFH1, and other PAK effectors, including LIMK1 and Merlin. PAK was also required for the thrombin-mediated activation of the MEK/ERK pathway, Akt, calcium signaling, and phosphatidylserine (PS) exposure. Inhibition of PAK signaling prevented thrombin-induced platelet aggregation and blocked platelet focal adhesion and lamellipodia formation in response to thrombin. Together, these results demonstrate that the PAK signaling system is a key orchestrator of platelet actin dynamics, linking Rho GTPase activation downstream of thrombin stimulation to PAK effector function, MAP kinase activation, calcium signaling, and PS exposure in platelets.

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“…In this context, we note that while LIMK1 -/- platelets showed reduced actin polymerization only late after stimulation [58], the specific inhibition of the Rho kinase that phosphorylates and activates LIMK1 results in significant F-actin level increase in unstimulated platelets [19]. This finding is reminiscent of the increased F-actin ratios in Pdlim7-deficient platelets (Fig 8).…”

Section: Discussionmentioning

confidence: 89%

Pdlim7 Regulates Arf6-Dependent Actin Dynamics and Is Required for Platelet-Mediated Thrombosis in Mice

et al. 2016

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Upon vessel injury, platelets become activated and rapidly reorganize their actin cytoskeleton to adhere to the site of endothelial damage, triggering the formation of a fibrin-rich plug to prevent further blood loss. Inactivation of Pdlim7 provides the new perspective that regulation of actin cytoskeletal changes in platelets is dependent on the encoded PDZ-LIM protein. Loss-of-function of Pdlim7 triggers hypercoagulopathy and causes significant perinatal lethality in mice. Our in vivo and in vitro studies reveal that Pdlim7 is dynamically distributed along actin fibers, and lack of Pdlim7 leads to a marked inability to rearrange the actin cytoskeleton. Specifically, the absence of Pdlim7 prevents platelets from bundling actin fibers into a concentric ring that defines the round spread shape of activated platelets. Similarly, in mouse embryonic fibroblasts, loss of Pdlim7 abolishes the formation of stress fibers needed to adopt the typical elongated fibroblast shape. In addition to revealing a fundamental cell biological role in actin cytoskeletal organization, we also demonstrate a function of Pdlim7 in regulating the cycling between the GTP/GDP-bound states of Arf6. The small GTPase Arf6 is an essential factor required for actin dynamics, cytoskeletal rearrangements, and platelet activation. Consistent with our findings of significantly elevated initial F-actin ratios and subsequent morphological aberrations, loss of Pdlim7 causes a shift in balance towards an increased Arf6-GTP level in resting platelets. These findings identify a new Pdlim7-Arf6 axis controlling actin dynamics and implicate Pdlim7 as a primary endogenous regulator of platelet-dependent hemostasis.

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LIM kinase-1 selectively promotes glycoprotein Ib-IX–mediated TXA2 synthesis, platelet activation, and thrombosis

Cited by 36 publications

References 41 publications

LIM kinase/cofilin dysregulation promotes macrothrombocytopenia in severe von Willebrand disease-type 2B

LIM kinase/cofilin dysregulation promotes macrothrombocytopenia in severe von Willebrand disease-type 2B

The PAK system links Rho GTPase signaling to thrombin-mediated platelet activation

Pdlim7 Regulates Arf6-Dependent Actin Dynamics and Is Required for Platelet-Mediated Thrombosis in Mice

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