Regulation of integrin trafficking, cell adhesion, and cell migration by WASH and the Arp2/3 complex

Duleh, Steve N.; Welch, Matthew D.

doi:10.1002/cm.21069

Cited by 34 publications

(44 citation statements)

References 51 publications

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“…23,24 Arf6 affects the routing between 2 integrin recycling pathways: a Rab4-mediated fast-recycling pathway and a Rab11-mediated slow-recycling pathway. 19,22 Rab4 and Rab11 are present but did not colocalize suggesting that platelets contain both early and recycling endosomes ( Figure 6A).…”

Section: Discussionmentioning

confidence: 99%

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Arf6 controls platelet spreading and clot retraction via integrin αIIbβ3 trafficking

Huang¹,

Joshi²,

Xiang

et al. 2016

Blood

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• Arf6 selectively regulates endocytic trafficking of platelet a IIb b 3 .• Endocytosis contributes to acute platelet function.Platelet and megakaryocyte endocytosis is important for loading certain granule cargo (ie, fibrinogen [Fg] and vascular endothelial growth factor); however, the mechanisms of platelet endocytosis and its functional acute effects are understudied. Adenosine 5'-diphosphate-ribosylation factor 6 (Arf6) is a small guanosine triphosphate-binding protein that regulates endocytic trafficking, especially of integrins. To study platelet endocytosis, we generated platelet-specific Arf6 knockout (KO) mice. Arf6 KO platelets had less associated Fg suggesting that Arf6 affects a IIb b 3 -mediated Fg uptake and/or storage. Other cargo was unaffected. To measure Fg uptake, mice were injected with biotinylated-or fluorescein isothiocyanate (FITC)-labeled Fg. Platelets from the injected Arf6 KO mice showed lower accumulation of tagged Fg, suggesting an uptake defect. Ex vivo, Arf6 KO platelets were also defective in FITC-Fg uptake and storage. Immunofluorescence analysis showed initial trafficking of FITC-Fg to a Rab4-positive compartment followed by colocalization with Rab11-positive structures, suggesting that platelets contain and use both early and recycling endosomes. Resting and activated a IIb b 3 levels, as measured by flow cytometry, were unchanged; yet, Arf6 KO platelets exhibited enhanced spreading on Fg and faster clot retraction. This was not the result of alterations in a IIb b 3 signaling, because myosin light-chain phosphorylation and Rac1/RhoA activation were unaffected. Consistent with the enhanced clot retraction and spreading, Arf6 KO mice showed no deficits in tail bleeding or FeCl 3 -induced carotid injury assays. Our studies present the first mouse model for defining the functions of platelet endocytosis and suggest that altered integrin trafficking may affect the efficacy of platelet function. (Blood. 2016;127(11):1459-1467 IntroductionIt is increasingly clear that platelets are capable of different types of intracellular membrane trafficking. Platelet exocytosis and autophagy are critical for hemostasis. [1][2][3][4] Platelet endocytosis is important for granule cargo loading. Platelets selectively take up certain cargo (ie, fibrinogen [Fg] and vascular endothelial growth factor) from plasma and package it into a-granules. [5][6][7][8] However, the molecular mechanisms of platelet endocytosis are largely unknown. It is also unclear whether platelet endocytosis contributes to acute platelet functions beyond granule cargo loading. The goal of this study is to begin to address these fundamental questions.The Ras-like, small guanosine triphosphate (GTP)-binding proteins called adenosine 5'-diphosphate-ribosylation factors (Arf's), are key intracellular trafficking regulators. They cycle between inactive guanosine diphosphate (GDP)-bound and active GTP-bound states and are important for multiple functions (eg, actin cytoskeleton remodeling, lipid metabolism, and vesicle traffickin...

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Section: Discussionmentioning

confidence: 99%

“…These integrin recycling routes are critical for cell adhesion and for directional migration. 23,24 It has been suggested that trafficking of a IIb b 3 bound to Fg could modulate platelet function. 25 Based on its role in nucleated cells, we asked if Arf6 could modulate membrane trafficking and whether that was important in platelets.…”

Section: Introductionmentioning

confidence: 99%

Arf6 controls platelet spreading and clot retraction via integrin αIIbβ3 trafficking

Huang¹,

Joshi²,

Xiang

et al. 2016

Blood

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“…and β2-adrenoreceptor as well as in targeting the epidermal growth factor receptor (EGFR) to the lysosome (23,25,28,29,31). The WASH complex also directly interacts with the retromer sorting complex and is thus required for the specific retrieval of retromer cargos from several endocytic compartments (23,32).…”

Section: Significancementioning

confidence: 99%

“…However, the mechanisms underpinning protein sorting before degradation are poorly understood. WASH has been shown to drive the recycling of several plasma membrane proteins from sorting endosomes back to the cell surface (28,29,45). We therefore asked whether the early phase of WASH and retromer activity provides a way to recover plasma membrane components from nascent macropinosomes before degradation.…”

Section: Wash Drives Recycling Of Surface Proteins From Early Macropimentioning

confidence: 99%

“…In particular, significant progress has been made in defining the role of actin in the segregation and extraction of specific proteins (22). Many studies describe a role for the WASH (WASP and SCAR homolog) complex in driving endosomal actin polymerization (23)(24)(25)(26)(27)(28)(29)(30). WASH has been implicated in the endosome-to-surface trafficking of a number of cargos, including the transferrin receptor (TfnR), α5β1 integrins,…”

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WASH drives early recycling from macropinosomes and phagosomes to maintain surface phagocytic receptors

Buckley

Gopaldass

Bosmani

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Macropinocytosis is an ancient mechanism that allows cells to harvest nutrients from extracellular media, which also allows immune cells to sample antigens from their surroundings. During macropinosome formation, bulk plasma membrane is internalized with all its integral proteins. It is vital for cells to salvage these proteins before degradation, but the mechanisms for sorting them are not known. Here we describe the evolutionarily conserved recruitment of the WASH (WASP and SCAR homolog) complex to both macropinosomes and phagosomes within a minute of internalization. Using Dictyostelium, we demonstrate that WASH drives protein sorting and recycling from macropinosomes and is thus essential to maintain surface receptor levels and sustain phagocytosis. WASH functionally interacts with the retromer complex at both early and late phases of macropinosome maturation, but mediates recycling via retromer-dependent and -independent pathways. WASH mutants consequently have decreased membrane levels of integrins and other surface proteins. This study reveals an important pathway enabling cells to sustain macropinocytosis without bulk degradation of plasma membrane components.phagocytosis | macropinocytosis | WASH | Dictyostelium | trafficking

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Loss of p53 Enhances NF-κB-Dependent Lamellipodia Formation

et al. 2014

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Tumor suppressor p53 prevents tumorigenesis and tumor growth by suppressing the activation of several transcription factors, including nuclear factor-κB (NF-κB) and STAT3. On the other hand, p53 stimulates actin cytoskeleton remodeling and integrin-related signaling cascades. Here, we examined the p53-mediated link between regulation of the actin cytoskeleton and activation of NF-κB and STAT3 in MCF-7 cells and mouse embryonic fibroblasts (MEFs). In the absence of p53, STAT3 was constitutively activated. This activation was attenuated by depleting the expression of p65, a component of NF-κB. Integrin β3 expression and lamellipodia formation were also downregulated by NF-κB depletion. Inhibition of integrin αvβ3, Rac1 or Arp2/3, which diminished lamellipodia formation, suppressed STAT3 activation induced by p53 depletion. These results suggest that loss of p53 leads to STAT3 activation via NF-κB-dependent lamellipodia formation. Our study proposes a novel role for p53 in modulating the actin cytoskeleton through suppression of NF-κB, which restricts STAT3 activation.

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Regulation of integrin trafficking, cell adhesion, and cell migration by WASH and the Arp2/3 complex

Cited by 34 publications

References 51 publications

Arf6 controls platelet spreading and clot retraction via integrin αIIbβ3 trafficking

Arf6 controls platelet spreading and clot retraction via integrin αIIbβ3 trafficking

WASH drives early recycling from macropinosomes and phagosomes to maintain surface phagocytic receptors

Loss of p53 Enhances NF-κB-Dependent Lamellipodia Formation

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