C‐Cbl regulates c‐MPL receptor trafficking and its internalization

Märklin, Melanie; Tandler, Claudia; Kopp, Hans‐Georg; Hoehn, Kyle L.; Quintanilla-Martı́nez, Leticia; Müller, Martin; Saur, Sebastian

doi:10.1111/jcmm.15785

Cited by 7 publications

(15 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Analysis of c‐Mpl levels on the surface was performed by flow cytometry in non-stimulated or TPO-stimulated platelets (25 ng/ml, 30 min), as described ( Marklin et al, 2020 ), using anti-c-Mpl antibody (AMM2 clone), followed by staining with anti-CD41-FITC and anti-rat Cy5 antibodies.…”

Section: Methodsmentioning

confidence: 99%

“…All this suggests that in C3G-KO platelets, the negative feedback regulation of c-Mpl signaling might be altered. In platelets, c-Cbl is responsible for c-Mpl ubiquitination and degradation (Saur et al, 2010;Marklin et al, 2020). Therefore, we studied whether C3G participates in this c-Cbl function.…”

Section: C3g Regulates C-mpl Levelsmentioning

confidence: 99%

“…In platelets, TPO binds to its receptor, c-Mpl, and induces its endocytosis, recycling and degradation ( Hitchcock et al, 2008 ). This mechanism is driven by the E3 ubiquitin ligase c-Cbl, responsible for the ubiquitination of c-Mpl and its degradation by the proteasome and lysosome systems ( Saur et al, 2010 ; Marklin et al, 2020 ). C-Cbl is phosphorylated and activated by SFKs (Src family kinases), such as Lyn ( Murphy et al, 2013 ), Fyn ( Hunter et al, 1999 ) and Src ( Yokouchi et al, 2001 ).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

New functions of C3G in platelet biology: Contribution to ischemia-induced angiogenesis, tumor metastasis and TPO clearance

Hernández-Cano

Fernández-Infante²,

Herranz³

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

C3G is a Rap1 guanine nucleotide exchange factor that controls platelet activation, aggregation, and the release of α-granule content. Transgenic expression of C3G in platelets produces a net proangiogenic secretome through the retention of thrombospondin-1. In a physiological context, C3G also promotes megakaryocyte maturation and proplatelet formation, but without affecting mature platelet production. The aim of this work is to investigate whether C3G is involved in pathological megakaryopoiesis, as well as its specific role in platelet mediated angiogenesis and tumor metastasis. Using megakaryocyte-specific C3G knockout and transgenic mouse models, we found that both C3G overexpression and deletion promoted platelet-mediated angiogenesis, induced by tumor cell implantation or hindlimb ischemia, through differential release of proangiogenic and antiangiogenic factors. However, only C3G deletion resulted in a higher recruitment of hemangiocytes from the bone marrow. In addition, C3G null expression enhanced thrombopoietin (TPO)-induced platelet production, associated with reduced TPO plasma levels. Moreover, after 5-fluorouracil-induced platelet depletion and rebound, C3G knockout mice showed a defective return to homeostatic platelet levels, indicating impaired platelet turnover. Mechanistically, C3G promotes c-Mpl ubiquitination by inducing Src-mediated c-Cbl phosphorylation and participates in c-Mpl degradation via the proteasome and lysosome systems, affecting TPO internalization. We also unveiled a positive role of platelet C3G in tumor cell-induced platelet aggregation, which facilitated metastatic cell homing and adhesion. Overall, these findings revealed that C3G plays a crucial role in platelet-mediated angiogenesis and metastasis, as well as in platelet level modulation in response to pathogenic stimuli.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: C3g Regulates C-mpl Levelsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

New functions of C3G in platelet biology: Contribution to ischemia-induced angiogenesis, tumor metastasis and TPO clearance

Hernández-Cano

Fernández-Infante²,

Herranz³

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…17 Mouse models lacking Mpl, the endocytic GTPase dynamin 2, or the ubiquitin ligase Cbl in platelets and MKs, where blunted TPO endocytosis results in hemapoietic stem and progenitor cell and MK hyperplasia related to increased TPO stimulation, support the role of Mpl-mediated endocytosis regulating TPO plasma levels. 26,36,37 Thrombocytosis is typically associated with thrombosis and thrombocytopenia with bleeding. Thus, the most confounding observation was the severe tail-bleeding diathesis and hemostatic defects of Jak2 Plt2/2 mice.…”

Section: Discussionmentioning

confidence: 99%

Bleeding diathesis in mice lacking JAK2 in platelets

et al. 2021

View full text Add to dashboard Cite

The tyrosine kinase JAK2 is a critical component of intracellular JAK/STAT cytokine signaling cascades that is prevalent in hematopoietic cells, such as hematopoietic stem cells and megakaryocytes (MKs). Individuals expressing the somatic JAK2 V617F mutation commonly develop myeloproliferative neoplasms (MPNs) associated with venous and arterial thrombosis, a leading cause of mortality. The role of JAK2 in hemostasis remains unclear. We investigated the role of JAK2 in platelet hemostatic function using Jak2fl/fl Pf4-Cre (Jak2Plt−/−) mice lacking JAK2 in platelets and MKs. Jak2Plt−/− mice developed MK hyperplasia and splenomegaly associated with severe thrombocytosis and bleeding. This notion was supported by failure to occlude in a ferric chloride carotid artery injury model and by a cremaster muscle laser-induced injury assay, in which Jak2Plt−/− platelets failed to form stable thrombi. Jak2Plt−/− platelets formed thrombi poorly after adhesion to type 1 collagen under arterial shear rates. Jak2Plt−/− platelets spread poorly on collagen under static conditions or on fibrinogen in response to the collagen receptor GPVI-specific agonist, collagen-related peptide (CRP). After activation with collagen, CRP, or the CLEC-2 agonist rhodocytin, Jak2Plt−/− platelets displayed decreased α-granule secretion and integrin αIIbβ3 activation or aggregation, but showed normal responses to thrombin. Jak2Plt−/− platelets had impaired intracellular signaling when activated via GPVI, as assessed by tyrosine phosphorylation. Together, the results show that JAK2 deletion impairs platelet immunoreceptor tyrosine-based activation motif signaling and hemostatic function in mice and suggest that aberrant JAK2 signaling in patients with MPNs affects GPVI signaling, leading to hemostatic platelet function.

show abstract

“…TPO in circulation binds the extracellular portion of predimerized c‐Mpl, likely resulting in a change of dimer arrangement equilibrium, activating signaling cascades within the cell and thus receptor phosphorylation 56 . Phosphorylated c‐Mpl is then internalized and undergoes proteasomal, via c‐Mpl ubiquitination, or lysosomal degradation within the cell, 57,58 contributing to the downregulation of circulating TPO levels. Studies have shown that reappearance of cell surface c‐Mpl is due to recycling of the internalized receptor rather than receptor reserve intracellular storage, 56,59 allowing for further TPO internalization.…”

Section: Prevailing Views Of Tpo Regulationmentioning

confidence: 99%

GPIbα is the driving force of hepatic thrombopoietin generation

Karakas

2021

Research and Practice in Thrombosis and Haemostasis

View full text Add to dashboard Cite

Thrombopoietin (TPO), a glycoprotein hormone produced predominantly in the liver, plays important roles in the hematopoietic stem cell (HSC) niche, and is essential for megakaryopoiesis and platelet generation. Long‐standing understanding proposes that TPO is constitutively produced by hepatocytes, and levels are fine‐tuned through platelet and megakaryocyte internalization/degradation via the c‐Mpl receptor. However, in immune thrombocytopenia (ITP) and several other diseases, TPO levels are inconsistent with this theory. Recent studies showed that platelets, besides their TPO clearance, can induce TPO production in the liver. Our group also accidentally discovered that platelet glycoprotein (GP) Ibα is required for platelet‐mediated TPO generation, which is underscored in both GPIbα −/− mice and patients with Bernard‐Soulier syndrome. This review will introduce platelet versatilities and several new findings in hemostasis and platelet consumption but focus on its roles in TPO regulation. The implications of these new discoveries in hematopoiesis and the HSC niche, particularly in ITP, will be discussed.

show abstract

C‐Cbl regulates c‐MPL receptor trafficking and its internalization

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 7 publications

References 48 publications

New functions of C3G in platelet biology: Contribution to ischemia-induced angiogenesis, tumor metastasis and TPO clearance

New functions of C3G in platelet biology: Contribution to ischemia-induced angiogenesis, tumor metastasis and TPO clearance

Bleeding diathesis in mice lacking JAK2 in platelets

GPIbα is the driving force of hepatic thrombopoietin generation

Contact Info

Product

Resources

About