Rasa3 deficiency minimally affects thrombopoiesis but promotes severe thrombocytopenia due to integrin-dependent platelet clearance

Lee, Robert H.; Ghalloussi, Dorsaf; Harousseau, Gabriel; Kenny, Joseph P.; Kramer, Patrick A.; Proamer, Fabienne; Nieswandt, Bernhard; Flick, Matthew J.; Gachet, Christian; Casari, Caterina; Eckly, Anita; Bergmeier, Wolfgang

doi:10.1172/jci.insight.155676

Cited by 9 publications

(4 citation statements)

References 56 publications

(79 reference statements)

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“…Lee et al. reported that platelets from mice bearing a hypomorphic Rasa3 mutant were entrapped in the spleen and liver, and subsequently they were engulfed by macrophages, presumably by talin1-dependent activation of integrin αIIbβ3, thus causing thrombocytopenia ( 46 ). The DKO T cells entrapped in the pulmonary capillaries probably transmigrate into the lung parenchyma, leading to accumulation in lung perivascular lymphatics that exclusively express CCL21.…”

Section: Discussionmentioning

confidence: 99%

The critical role of Rap1-GAPs Rasa3 and Sipa1 in T cells for pulmonary transit and egress from the lymph nodes

et al. 2023

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Rap1-GTPase activates integrins and plays an indispensable role in lymphocyte trafficking, but the importance of Rap1 inactivation in this process remains unknown. Here we identified the Rap1-inactivating proteins Rasa3 and Sipa1 as critical regulators of lymphocyte trafficking. The loss of Rasa3 and Sipa1 in T cells induced spontaneous Rap1 activation and adhesion. As a consequence, T cells deficient in Rasa3 and Sipa1 were trapped in the lung due to firm attachment to capillary beds, while administration of LFA1 antibodies or loss of talin1 or Rap1 rescued lung sequestration. Unexpectedly, mutant T cells exhibited normal extravasation into lymph nodes, fast interstitial migration, even greater chemotactic responses to chemokines and sphingosine-1-phosphate, and entrance into lymphatic sinuses but severely delayed exit: mutant T cells retained high motility in lymphatic sinuses and frequently returned to the lymph node parenchyma, resulting in defective egress. These results reveal the critical trafficking processes that require Rap1 inactivation.

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Section: Discussionmentioning

confidence: 99%

The critical role of Rap1-GAPs Rasa3 and Sipa1 in T cells for pulmonary transit and egress from the lymph nodes

et al. 2023

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“…Inactivation of Rasa3 in mouse had a megakaryocytic dysplasia accompanied with a severe thrombocytopenia, and these megakaryocyte alterations were related to an increased active Rap1 level and a constitutive integrin activation [94,95]. However, a new molecular mechanism has been found that dysregulated integrin signaling in the Rasa3-mutant mouse model may contribute to increased platelet clearance in various inherited and acquired thrombocytopenia [96].…”

Section: The Other Members Of Ras Subfamilymentioning

confidence: 99%

Insights into Regulatory Factors in Megakaryocyte Development and Function: Basic Mechanisms and Potential Targets

Li¹,

Ni²,

Ming³

et al. 2022

Front. Biosci. (Landmark Ed)

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Platelets are small, anucleate cellular fragments, which are produced by megakaryocytes, and play a key role in hemostasis and thrombus formation. The differentiation of megakaryocytes from hematopoietic stem cells in bone marrow and the development of megakaryocytes into platelets is a complex process. Various regulatory factorsin megakaryopoiesis including cytokines, growth factors, transcription factors, and gene expression, are all involved in the process of thrombocytopoiesis and play distinct roles in different stages of megakaryocytes development. In this review, we summarize the current state of knowledge ofmultiple regulatory factors including the TPO/Mpl signaling pathway, transcription factors, RasGTPases family, estrogen, and microRNAs. Altogether, we aimed to discuss more molecular mechanisms of megakaryocytes differentiation and maturation, and possess a better understanding of platelet formation.

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“…RASA3 is a ubiquitously expressed GTPase‐activating protein that inhibits R‐Ras and Rap1 activity. 17 , 18 , 19 , 20 , 21 Global loss of RASA3 expression in mice is embryonically lethal due to failure of vasculogenesis and severe bleeding. 22 Conditional endothelial cell‐specific knockout of RASA3 in mice recapitulates failure of vascular lumen formation and decreased vascular complexity.…”

Section: Introductionmentioning

confidence: 99%

“…RASA3 is a ubiquitously expressed GTPase‐activating protein that inhibits R‐Ras and Rap1 activity 17–21 . Global loss of RASA3 expression in mice is embryonically lethal due to failure of vasculogenesis and severe bleeding 22 .…”

Section: Introductionmentioning

confidence: 99%

RASA3 is a candidate gene in sickle cell disease‐associated pulmonary hypertension and pulmonary arterial hypertension

et al. 2023

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Pulmonary hypertension (PH) is associated with significant morbidity and mortality. RASA3 is a GTPase activating protein integral to angiogenesis and endothelial barrier function. In this study, we explore the association of RASA3 genetic variation with PH risk in patients with sickle cell disease (SCD)‐associated PH and pulmonary arterial hypertension (PAH). Cis ‐expression quantitative trait loci (eQTL) were queried for RASA3 using whole genome genotype arrays and gene expression profiles derived from peripheral blood mononuclear cells (PBMC) of three SCD cohorts. Genome‐wide single nucleotide polymorphisms (SNPs) near or in the RASA3 gene that may associate with lung RASA3 expression were identified, reduced to 9 tagging SNPs for RASA3 and associated with markers of PH. Associations between the top RASA3 SNP and PAH severity were corroborated using data from the PAH Biobank and analyzed based on European or African ancestry (EA, AA). We found that PBMC RASA3 expression was lower in patients with SCD‐associated PH as defined by echocardiography and right heart catheterization and was associated with higher mortality. One eQTL for RASA3 (rs9525228) was identified, with the risk allele correlating with PH risk, higher tricuspid regurgitant jet velocity and higher pulmonary vascular resistance in patients with SCD‐associated PH. rs9525228 associated with markers of precapillary PH and decreased survival in individuals of EA but not AA. In conclusion, RASA3 is a novel candidate gene in SCD‐associated PH and PAH, with RASA3 expression appearing to be protective. Further studies are ongoing to delineate the role of RASA3 in PH.

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Rasa3 deficiency minimally affects thrombopoiesis but promotes severe thrombocytopenia due to integrin-dependent platelet clearance

Cited by 9 publications

References 56 publications

The critical role of Rap1-GAPs Rasa3 and Sipa1 in T cells for pulmonary transit and egress from the lymph nodes

The critical role of Rap1-GAPs Rasa3 and Sipa1 in T cells for pulmonary transit and egress from the lymph nodes

Insights into Regulatory Factors in Megakaryocyte Development and Function: Basic Mechanisms and Potential Targets

RASA3 is a candidate gene in sickle cell disease‐associated pulmonary hypertension and pulmonary arterial hypertension

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