Headpiece Domain of Dematin Regulates Calcium Mobilization and Signaling in Platelets

Wieschhaus, Adam J.; Breton, Guy C. Le; Chishti, Athar H.

doi:10.1074/jbc.m112.364679

Cited by 3 publications

(1 citation statement)

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“…4,29 Dematin regulates calcium mobilization, RhoA activity, cell shape, and cell migration in nonerythroid cells. [30][31][32] Despite much effort, the physiologic function of RBC dematin remains poorly understood. Gene targeting and global transcript analysis revealed dematin as a major target of EKLF, 33,34 an erythroidspecific transcription factor that is essential for the regulation of definitive erythropoiesis.…”

Section: Discussionmentioning

confidence: 99%

Gene disruption of dematin causes precipitous loss of erythrocyte membrane stability and severe hemolytic anemia

Hanada

Fujiwara

et al. 2016

Blood

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• Genetic deletion of full-length mouse dematin causes severe abnormalities of erythrocyte shape, membrane stability, and hemolytic anemia.• Dematin is critical for the junctional complex integrity.Dematin is a relatively low abundance actin binding and bundling protein associated with the spectrin-actin junctions of mature erythrocytes. Primary structure of dematin includes a loosely folded core domain and a compact headpiece domain that was originally identified in villin. Dematin's actin binding properties are regulated by phosphorylation of its headpiece domain by cyclic adenosine monophosphate-dependent protein kinase.Here, we used a novel gene disruption strategy to generate the whole body dematin gene knockout mouse model (FLKO). FLKO mice, while born at a normal Mendelian ratio, developed severe anemia and exhibited profound aberrations of erythrocyte morphology and membrane stability. Having no apparent effect on primitive erythropoiesis, FLKO mice show significant enhancement of erythroblast enucleation during definitive erythropoiesis. Using membrane protein analysis, domain mapping, electron microscopy, and dynamic deformability measurements, we investigated the mechanism of membrane instability in FLKO erythrocytes. Although many membrane and cytoskeletal proteins remained at their normal levels, the major peripheral membrane proteins spectrin, adducin, and actin were greatly reduced in FLKO erythrocytes. Our results demonstrate that dematin plays a critical role in maintaining the fundamental properties of the membrane cytoskeleton complex. (Blood. 2016;128(1):93-103)

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