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PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation
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| Zeitschriftentitel: | Blood |
|---|---|
| Personen und Körperschaften: | , , , , , |
| In: | Blood, 108, 2006, 13, S. 4035-4044 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society of Hematology
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| Schlagwörter: |
| author_facet |
Pula, Giordano Schuh, Kai Nakayama, Keiko Nakayama, Keiichi I. Walter, Ulrich Poole, Alastair W. Pula, Giordano Schuh, Kai Nakayama, Keiko Nakayama, Keiichi I. Walter, Ulrich Poole, Alastair W. |
|---|---|
| author |
Pula, Giordano Schuh, Kai Nakayama, Keiko Nakayama, Keiichi I. Walter, Ulrich Poole, Alastair W. |
| spellingShingle |
Pula, Giordano Schuh, Kai Nakayama, Keiko Nakayama, Keiichi I. Walter, Ulrich Poole, Alastair W. Blood PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation Cell Biology Hematology Immunology Biochemistry |
| author_sort |
pula, giordano |
| spelling |
Pula, Giordano Schuh, Kai Nakayama, Keiko Nakayama, Keiichi I. Walter, Ulrich Poole, Alastair W. 0006-4971 1528-0020 American Society of Hematology Cell Biology Hematology Immunology Biochemistry http://dx.doi.org/10.1182/blood-2006-05-023739 <jats:title>Abstract</jats:title><jats:p>Protein kinase Cδ (PKCδ) has been shown by pharmacologic approaches to negatively regulate collagen-induced platelet aggregation. Here we addressed the molecular and cellular mechanisms underlying this negative regulation. Using PKCδ–/– platelets, we show that the mechanism did not involve altered inside-out signaling to integrin αIIbβ3 and did not affect early signaling events downstream of GPVI, because there was no difference in tyrosine phosphorylation of PLCγ2 between wild-type and PKCδ–/– platelets. There was also no increase in secretion of dense granule content, in contrast to studies using rottlerin where secretion was enhanced. Importantly, however, there was marked enhancement of filopodia generation in PKCδ–/– platelets upon adhesion to collagen compared with wild-type platelets. Filopodia play an essential role regulating adhesive events leading to platelet aggregation by increasing platelet-platelet contact. We show that the critical effector for PKCδ is vasodilator-stimulated phosphoprotein (VASP), a major regulator of actin cytoskeleton dynamics. PKCδ physically interacts with VASP constitutively and regulates its phosphorylation on Ser157. In VASP–/– platelets, the enhancement of filopodia generation, actin polymerization, and platelet aggregation by rottlerin is ablated. PKCδ is therefore a critical negative regulator of filopodia, and hence platelet aggregation, through a functional interaction with the actin organizer VASP.</jats:p> PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation Blood |
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| title |
PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation |
| title_unstemmed |
PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation |
| title_full |
PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation |
| title_fullStr |
PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation |
| title_full_unstemmed |
PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation |
| title_short |
PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation |
| title_sort |
pkcδ regulates collagen-induced platelet aggregation through inhibition of vasp-mediated filopodia formation |
| topic |
Cell Biology Hematology Immunology Biochemistry |
| url |
http://dx.doi.org/10.1182/blood-2006-05-023739 |
| publishDate |
2006 |
| physical |
4035-4044 |
| description |
<jats:title>Abstract</jats:title><jats:p>Protein kinase Cδ (PKCδ) has been shown by pharmacologic approaches to negatively regulate collagen-induced platelet aggregation. Here we addressed the molecular and cellular mechanisms underlying this negative regulation. Using PKCδ–/– platelets, we show that the mechanism did not involve altered inside-out signaling to integrin αIIbβ3 and did not affect early signaling events downstream of GPVI, because there was no difference in tyrosine phosphorylation of PLCγ2 between wild-type and PKCδ–/– platelets. There was also no increase in secretion of dense granule content, in contrast to studies using rottlerin where secretion was enhanced. Importantly, however, there was marked enhancement of filopodia generation in PKCδ–/– platelets upon adhesion to collagen compared with wild-type platelets. Filopodia play an essential role regulating adhesive events leading to platelet aggregation by increasing platelet-platelet contact. We show that the critical effector for PKCδ is vasodilator-stimulated phosphoprotein (VASP), a major regulator of actin cytoskeleton dynamics. PKCδ physically interacts with VASP constitutively and regulates its phosphorylation on Ser157. In VASP–/– platelets, the enhancement of filopodia generation, actin polymerization, and platelet aggregation by rottlerin is ablated. PKCδ is therefore a critical negative regulator of filopodia, and hence platelet aggregation, through a functional interaction with the actin organizer VASP.</jats:p> |
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| author | Pula, Giordano, Schuh, Kai, Nakayama, Keiko, Nakayama, Keiichi I., Walter, Ulrich, Poole, Alastair W. |
| author_facet | Pula, Giordano, Schuh, Kai, Nakayama, Keiko, Nakayama, Keiichi I., Walter, Ulrich, Poole, Alastair W., Pula, Giordano, Schuh, Kai, Nakayama, Keiko, Nakayama, Keiichi I., Walter, Ulrich, Poole, Alastair W. |
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| description | <jats:title>Abstract</jats:title><jats:p>Protein kinase Cδ (PKCδ) has been shown by pharmacologic approaches to negatively regulate collagen-induced platelet aggregation. Here we addressed the molecular and cellular mechanisms underlying this negative regulation. Using PKCδ–/– platelets, we show that the mechanism did not involve altered inside-out signaling to integrin αIIbβ3 and did not affect early signaling events downstream of GPVI, because there was no difference in tyrosine phosphorylation of PLCγ2 between wild-type and PKCδ–/– platelets. There was also no increase in secretion of dense granule content, in contrast to studies using rottlerin where secretion was enhanced. Importantly, however, there was marked enhancement of filopodia generation in PKCδ–/– platelets upon adhesion to collagen compared with wild-type platelets. Filopodia play an essential role regulating adhesive events leading to platelet aggregation by increasing platelet-platelet contact. We show that the critical effector for PKCδ is vasodilator-stimulated phosphoprotein (VASP), a major regulator of actin cytoskeleton dynamics. PKCδ physically interacts with VASP constitutively and regulates its phosphorylation on Ser157. In VASP–/– platelets, the enhancement of filopodia generation, actin polymerization, and platelet aggregation by rottlerin is ablated. PKCδ is therefore a critical negative regulator of filopodia, and hence platelet aggregation, through a functional interaction with the actin organizer VASP.</jats:p> |
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| imprint | American Society of Hematology, 2006 |
| imprint_str_mv | American Society of Hematology, 2006 |
| institution | DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161, DE-Zi4, DE-Gla1, DE-15, DE-Pl11, DE-Rs1, DE-14, DE-105, DE-Ch1, DE-L229 |
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| last_indexed | 2024-03-01T15:51:09.759Z |
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| spelling | Pula, Giordano Schuh, Kai Nakayama, Keiko Nakayama, Keiichi I. Walter, Ulrich Poole, Alastair W. 0006-4971 1528-0020 American Society of Hematology Cell Biology Hematology Immunology Biochemistry http://dx.doi.org/10.1182/blood-2006-05-023739 <jats:title>Abstract</jats:title><jats:p>Protein kinase Cδ (PKCδ) has been shown by pharmacologic approaches to negatively regulate collagen-induced platelet aggregation. Here we addressed the molecular and cellular mechanisms underlying this negative regulation. Using PKCδ–/– platelets, we show that the mechanism did not involve altered inside-out signaling to integrin αIIbβ3 and did not affect early signaling events downstream of GPVI, because there was no difference in tyrosine phosphorylation of PLCγ2 between wild-type and PKCδ–/– platelets. There was also no increase in secretion of dense granule content, in contrast to studies using rottlerin where secretion was enhanced. Importantly, however, there was marked enhancement of filopodia generation in PKCδ–/– platelets upon adhesion to collagen compared with wild-type platelets. Filopodia play an essential role regulating adhesive events leading to platelet aggregation by increasing platelet-platelet contact. We show that the critical effector for PKCδ is vasodilator-stimulated phosphoprotein (VASP), a major regulator of actin cytoskeleton dynamics. PKCδ physically interacts with VASP constitutively and regulates its phosphorylation on Ser157. In VASP–/– platelets, the enhancement of filopodia generation, actin polymerization, and platelet aggregation by rottlerin is ablated. PKCδ is therefore a critical negative regulator of filopodia, and hence platelet aggregation, through a functional interaction with the actin organizer VASP.</jats:p> PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation Blood |
| spellingShingle | Pula, Giordano, Schuh, Kai, Nakayama, Keiko, Nakayama, Keiichi I., Walter, Ulrich, Poole, Alastair W., Blood, PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation, Cell Biology, Hematology, Immunology, Biochemistry |
| title | PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation |
| title_full | PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation |
| title_fullStr | PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation |
| title_full_unstemmed | PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation |
| title_short | PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation |
| title_sort | pkcδ regulates collagen-induced platelet aggregation through inhibition of vasp-mediated filopodia formation |
| title_unstemmed | PKCδ regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation |
| topic | Cell Biology, Hematology, Immunology, Biochemistry |
| url | http://dx.doi.org/10.1182/blood-2006-05-023739 |