Dok-2 Adaptor Protein Regulates the Shear-dependent Adhesive Function of Platelet Integrin αIIbβ3 in Mice

Abstract

Background: Dok proteins are negative regulators of immunoreceptor signaling and, potentially, integrin adhesion receptors. Results: Deficiency of Dok-2 results in enhanced shear-dependent integrin adhesion in platelets, leading to accelerated platelet thrombus growth. Conclusion: Dok-2 is a shear-specific negative regulator of blood clot formation. Significance: Dok-2 regulates biomechanical platelet adhesion, and targeting this molecule may provide new avenues to regulate thrombosis.

Compression force sensing regulates integrin αIIbβ3 adhesive function on diabetic platelets

“…Hyperglycemia (blood glucose levels of >15 mM) was confirmed 1 week post streptozotocin injection and in vivo thrombosis studies were performed on mice 7–10 weeks post streptozotocin injection. In initial studies, we investigated the impact of disturbed blood flow on the platelet aggregation response in diabetic mice using a needle in situ model of platelet thrombus formation 32 , 33 . In this model, the tip of a microinjector needle is inserted into the center of the lumen of a mesenteric vessel, creating a local region of flow disturbance (Fig.…”

Tension on JAM-A activates RhoA via GEF-H1 and p115 RhoGEF

“…This is not surprising, because SFKs are known to be regulated by mechanical forces. SFK family members Fyn ( Kostic and Sheetz, 2006 ; Chiu et al ., 2008 ; Guilluy et al ., 2011b ; Fiore et al ., 2015 ), Src ( Chaturvedi et al ., 2007 ; Wijetunge and Hughes, 2007 ), Yes ( Niediek et al ., 2012 ), and Lyn ( Alessandri-Haber et al ., 2008 ; Hughan et al ., 2014 ) are all activated in response to mechanical forces. Because SFKs are activated by force and Su6656 inhibits multiple SFKs ( Blake et al ., 2000 ), it is difficult to determine which kinase(s) are involved without extensive investigation.…”

“…JAM-A also plays a critical role when expressed at cell–cell junctions, as absence of the protein affects the mechanical properties of the cell ( Hughan et al ., 2014 ; Tornavaca et al ., 2015 ). Breast cancer provides an intriguing model for the present work.…”

Integrin αIIbβ3 outside-in signaling

“…121,122 Beyond those discussed earlier, a range of further proteins can have either positive or negative roles in a IIb b 3 integrin outside-in signaling, including lymphocyte adaptor protein (Lnk)-and downstream of tyrosine kinase (DOK)-family proteins, respectively (Table 1). [137][138][139] Protein phosphatases contribute to outside-in signaling to regulate clot retraction, 140 whereas the PtdIns(3,4,5)P 3 phosphatase SH2-containing inositol-59-phosphatase 1 (SHIP-1) enables a IIb b 3 outside-in signaling to restrain excessive platelet activation. 141 Integrins can also crosstalk with other cell-surface proteins/receptors to mediate outside-in signaling, and a IIb b 3 makes functionally important interactions with tetraspanins such as CD151 and tumor-suppressing subchromosomal transferable fragment cDNA 6 (TSSC6).…”