Analysis of Fyn function in hemostasis and αIIbβ3-integrin signaling

Reddy, Kumar B.; Smith, Dawn; Plow, Edward F.

doi:10.1242/jcs.014076

Cited by 59 publications

(68 citation statements)

References 54 publications

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“…In HeLa cells, Fyn-mRFP was present throughout the plasma membrane, and was apparently enriched in focal adhesions (Reddy et al, 2008). TIR microscopy revealed that Fyn-mRFP had a more uniform distribution than flotillin-1-GFP, and was visibly concentrated in less than 5% of flotillin microdomains (Fig.…”

Section: Et Al 2001mentioning

confidence: 93%

Endocytosis of flotillin-1 and flotillin-2 is regulated by Fyn kinase

Riento

Frick

Schäfer

et al. 2009

Journal of Cell Science

125

145

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Flotillin-1 and flotillin-2 co-assemble into plasma membrane microdomains that are involved in the endocytosis of molecules such as glycosyl phosphatidylinositol (GPI)-linked proteins. Previous studies suggest that budding of flotillin microdomains from the plasma membrane is a tightly regulated process. Here, we demonstrate that endocytosis of flotillins is regulated by the Src family kinase Fyn. The Src kinase inhibitor PP2 prevents EGF-induced flotillin internalisation, and EGF-induced internalisation does not occur in SYF cells lacking Src, Yes and Fyn. Expression of Fyn, but not Src or Yes, restores EGF-induced internalisation in SYF cells. Expression of an active form of Fyn but not other Src kinases is sufficient to induce redistribution of flotillins from the plasma membrane to late endosomes and lysosomes. Using two partial Fyn constructs that form a functional kinase upon addition of rapamycin to cells, we show that flotillin internalisation from the plasma membrane occurs shortly after Fyn activation. Tyr160 in flotillin-1 and Tyr163 in flotillin-2 are directly phosphorylated by Fyn, and mutation of these residues to phenylalanine prevents Fyn-induced flotillin internalisation. Uptake of the GPI-linked protein CD59 is reduced by expression of the phenylalanine-mutated flotillins. These data establish uptake of flotillin microdomains as a tyrosine-kinase-regulated endocytic process.

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Section: Et Al 2001mentioning

confidence: 93%

Endocytosis of flotillin-1 and flotillin-2 is regulated by Fyn kinase

Riento

Frick

Schäfer

et al. 2009

Journal of Cell Science

125

145

View full text Add to dashboard Cite

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“…SFKs can bind directly to β-integrin tails in a tail-and SFK-specific manner, and this interaction contributes to activation of kinase activity and controls cell spreading (Arias-Salgado et al, 2003;Reddy et al, 2008). SFKs also bind to and phosphorylate FAK and FAK-binding proteins.…”

Section: Src-family Kinasesmentioning

confidence: 99%

Integrin signalling at a glance

Harburger

Calderwood

2009

Journal of Cell Science

768

506

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There was an error published in J. Cell Sci. 122, 159-163.It has been brought to our attention that there is an error in the poster published in association with this article. Non-phosphorylated ICAP1 is shown to bind to the cytoplasmic tails of integrin β-subunits, whereas Ca 2+ /calmodulin-dependent protein kinase II (CaMKII)-mediated phosphorylation of ICAP1 is depicted as driving dissociation of ICAP1 from integrin β-tails. Although ICAP1 is indeed a substrate for CaMKII, the phosphorylation of ICAP1 on Thr38 is likely to enhance ICAP1 binding to β1 tails rather than inhibit the interaction, and this might account for CaMKII-mediated inhibition of α5β1 activation (Bouvard et al., 1998; Bouvard and Block, 1998).The authors apologise for this mistake and for any confusion caused.

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“…62 Loss of the Src binding site is thought to be calpain-mediated. 63 Fyn-deficient mouse platelets exhibit a less severe spreading defect on fibrinogen compared with Srcdeficient platelets, demonstrating the dominant role of Src downstream of aIIbb3.…”

Section: 51mentioning

confidence: 99%

Src family kinases: at the forefront of platelet activation

Senis

Mazharian

Mori

2014

Blood

247

214

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Src family kinases (SFKs) play a central role in mediating the rapid response of platelets to vascular injury. They transmit activation signals from a diverse repertoire of platelet surface receptors, including the integrin αIIbβ3, the immunoreceptor tyrosine–based activation motif–containing collagen receptor complex GPVI-FcR γ-chain, and the von Willebrand factor receptor complex GPIb-IX-V, which are essential for thrombus growth and stability. Ligand-mediated clustering of these receptors triggers an increase in SFK activity and downstream tyrosine phosphorylation of enzymes, adaptors, and cytoskeletal proteins that collectively propagate the signal and coordinate platelet activation. A growing body of evidence has established that SFKs also contribute to Gq- and Gi-coupled receptor signaling that synergizes with primary activation signals to maximally activate platelets and render them prothrombotic. Interestingly, SFKs concomitantly activate inhibitory pathways that limit platelet activation and thrombus size. In this review, we discuss past discoveries that laid the foundation for this fundamental area of platelet signal transduction, recent progress in our understanding of the distinct and overlapping functions of SFKs in platelets, and new avenues of research into mechanisms of SFK regulation. We also highlight the thrombotic and hemostatic consequences of targeting platelet SFKs.

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Analysis of Fyn function in hemostasis and αIIbβ3-integrin signaling

Cited by 59 publications

References 54 publications

Endocytosis of flotillin-1 and flotillin-2 is regulated by Fyn kinase

Endocytosis of flotillin-1 and flotillin-2 is regulated by Fyn kinase

Integrin signalling at a glance

Src family kinases: at the forefront of platelet activation

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