Header

UZH-Logo

Maintenance Infos

Profilin 1-mediated cytoskeletal rearrangements regulate integrin function in mouse platelets


Stritt, Simon; Birkholz, Inga; Beck, Sarah; Sorrentino, Simona; Sapra, K Tanuj; Viaud, Julien; Heck, Johannes; Gaits-Iacovoni, Frédérique; Schulze, Harald; Du, Xiaoping; Hartwig, John H; Braun, Attila; Bender, Markus; Medalia, Ohad; Nieswandt, Bernhard (2018). Profilin 1-mediated cytoskeletal rearrangements regulate integrin function in mouse platelets. Blood advances, 2(9):1040-1045.

Abstract

Platelet adhesion and aggregation at sites of vascular injury is essential for hemostasis but may also cause thrombosis.1 Firm platelet adhesion is mediated by heterodimeric receptors of the β1- and β3-integrin families, which upon activation reversibly shift to a high-affinity state and efficiently bind their ligands, most notably components of the extracellular matrix and other receptors.2⇓-4 Binding of talin-1 (Tln1) and kindlins to the intracellular tail of the integrin β-subunit triggers the switch to the high-affinity state, whereas their dissociation results in integrin closure, the switch back to the low-affinity state.5⇓⇓-8 Tln1 and kindlins connect integrins to the actin cytoskeleton, thereby enabling the sensing and exertion of mechanical forces as well as regulating adhesion formation and turnover.9⇓⇓-12 Consistently, defects in actin-regulating proteins result in altered platelet and megakaryocyte integrin function.13⇓⇓⇓⇓⇓-19 Furthermore, we have recently shown a critical role of twinfilin 2a (Twf2a) and the cortical cytoskeleton in regulating platelet integrin turnover in a profilin 1 (Pfn1)–dependent manner.10 The small actin-binding protein Pfn1 is central for actin dynamics by mediating the nucleotide exchange on G-actin monomers, thereby promoting filament assembly with implications for platelet biogenesis.13,20 Megakaryocyte-specific Pfn1 deficiency resulted in microthrombocytopenia because of cytoskeletal alterations and accelerated platelet clearance (supplemental Figure 1).13 However, the precise role of Pfn1 for platelet function is unknown. Here, we report that the lack of Pfn1 in platelets (Pfn1fl/fl-Pf4Cre) perturbs the organization of the adhesion-dependent circumferential actin network and thereby results in accelerated integrin inactivation and hence impaired platelet function in vitro and in vivo.

Abstract

Platelet adhesion and aggregation at sites of vascular injury is essential for hemostasis but may also cause thrombosis.1 Firm platelet adhesion is mediated by heterodimeric receptors of the β1- and β3-integrin families, which upon activation reversibly shift to a high-affinity state and efficiently bind their ligands, most notably components of the extracellular matrix and other receptors.2⇓-4 Binding of talin-1 (Tln1) and kindlins to the intracellular tail of the integrin β-subunit triggers the switch to the high-affinity state, whereas their dissociation results in integrin closure, the switch back to the low-affinity state.5⇓⇓-8 Tln1 and kindlins connect integrins to the actin cytoskeleton, thereby enabling the sensing and exertion of mechanical forces as well as regulating adhesion formation and turnover.9⇓⇓-12 Consistently, defects in actin-regulating proteins result in altered platelet and megakaryocyte integrin function.13⇓⇓⇓⇓⇓-19 Furthermore, we have recently shown a critical role of twinfilin 2a (Twf2a) and the cortical cytoskeleton in regulating platelet integrin turnover in a profilin 1 (Pfn1)–dependent manner.10 The small actin-binding protein Pfn1 is central for actin dynamics by mediating the nucleotide exchange on G-actin monomers, thereby promoting filament assembly with implications for platelet biogenesis.13,20 Megakaryocyte-specific Pfn1 deficiency resulted in microthrombocytopenia because of cytoskeletal alterations and accelerated platelet clearance (supplemental Figure 1).13 However, the precise role of Pfn1 for platelet function is unknown. Here, we report that the lack of Pfn1 in platelets (Pfn1fl/fl-Pf4Cre) perturbs the organization of the adhesion-dependent circumferential actin network and thereby results in accelerated integrin inactivation and hence impaired platelet function in vitro and in vivo.

Statistics

Citations

Dimensions.ai Metrics
3 citations in Web of Science®
3 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

28 downloads since deposited on 12 Jun 2018
9 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Health Sciences > Hematology
Language:English
Date:8 May 2018
Deposited On:12 Jun 2018 15:35
Last Modified:29 Jul 2020 07:19
Publisher:American Society of Hematology
ISSN:2473-9529
OA Status:Green
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1182/bloodadvances.2017014001
PubMed ID:29739775

Download

Green Open Access

Download PDF  'Profilin 1-mediated cytoskeletal rearrangements regulate integrin function in mouse platelets'.
Preview
Content: Published Version
Filetype: PDF
Size: 1MB
View at publisher