Lyn-mediated procaspase 8 dimerization blocks apoptotic signaling in B-cell chronic lymphocytic leukemia

Zonta, Francesca; Pagano, Mario A.; Trentin, Livio; Tibaldi, Elena; Frezzato, Federica; Gattazzo, Cristina; Martini, Veronica; Trimarco, Valentina; Mazzorana, Marco; Bordin, Luciana; Semenzato, Gianpietro; Brunati, Anna Maria

doi:10.1182/blood-2013-02-485540

Cited by 25 publications

(29 citation statements)

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“…To evaluate the role of Lyn's SH3 domain in the interaction with HSP90 or HSP70, we performed competition assays using recombinant Lyn SH3 domain. 14,29,32 The Lyn SH3 domain serves as an interaction domain for protein partners and as a regulatory domain for Lyn kinase. 14,29,32 Addition of GST-Lyn/SH3 domain failed to disrupt the interaction between Lyn and HSP90 or HSP70 ( Figure 2C; supplemental Figure 2B), confirming previous data in other cell models that highlighted the central role of the Lyn catalytic domain in binding HSP90.…”

Section: Resultsmentioning

confidence: 99%

“…14,29,32 The Lyn SH3 domain serves as an interaction domain for protein partners and as a regulatory domain for Lyn kinase. 14,29,32 Addition of GST-Lyn/SH3 domain failed to disrupt the interaction between Lyn and HSP90 or HSP70 ( Figure 2C; supplemental Figure 2B), confirming previous data in other cell models that highlighted the central role of the Lyn catalytic domain in binding HSP90. 32 These data together suggest that active Lyn in chorea-acanthocytosis erythrocytes is sequestered by chaperone machinery for either proteasomal degradation or rescue from degradation.…”

Section: Resultsmentioning

confidence: 99%

“…When required, the IP assays were carried out as required in the absence or presence of the GST-Lyn/SH3 domain or of the inhibitors PP2 or geldanamycin (GA). 29 …”

Section: Red Cell Membrane Cytosol Preparation Immunoblot Analysismentioning

confidence: 99%

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A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis

Lupo

Tibaldi

Mattè

et al. 2016

Blood

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Key Points• In chorea-acanthocytosis, spiculated red cells are characterized by heightened Lyn kinase activity and dysregulated autophagy.• Regulation of protein turnover by autophagy plays a key role in erythropoiesis and red cell integrity.Chorea-acanthocytosis is one of the hereditary neurodegenerative disorders known as the neuroacanthocytoses. Chorea-acanthocytosis is characterized by circulating acanthocytes deficient in chorein, a protein of unknown function. We report here for the first time that chorea-acanthocytosis red cells are characterized by impaired autophagy, with cytoplasmic accumulation of active Lyn and of autophagy-related proteins Ulk1 and Atg7. In chorea-acanthocytosis erythrocytes, active Lyn is sequestered by HSP90-70 to form high-molecular-weight complexes that stabilize and protect Lyn from its proteasomal degradation, contributing to toxic Lyn accumulation. An interplay between accumulation of active Lyn and autophagy was found in chorea-acanthocytosis based on Lyn coimmunoprecipitation with Ulk1 and Atg7 and on the presence of Ulk1 in Lyncontaining high-molecular-weight complexes. In addition, chorein associated with Atg7 in healthy but not in chorea-acanthocytosis erythrocytes. Electron microscopy detected multivesicular bodies and membrane remnants only in circulating chorea-acanthocytosis red cells. In addition, reticulocyte-enriched chorea-acanthocytosis red cell fractions exhibited delayed clearance of mitochondria and lysosomes, further supporting the impairment of authophagic flux. Because autophagy is also important in erythropoiesis, we studied in vitro CD341 -derived erythroid precursors. In chorea-acanthocytosis, we found (1) dyserythropoiesis; (2) increased active Lyn; (3) accumulation of a marker of autophagic flux and autolysososme degradation; (4) accumlation of Lamp1, a lysosmal membrane protein, and LAMP1-positive aggregates; and (5) reduced clearance of lysosomes and mitochondria. Our results uncover in choreaacanthocytosis erythroid cells an association between accumulation of active Lyn and impaired autophagy, suggesting a link between chorein and autophagic vesicle trafficking in erythroid maturation. (Blood. 2016;128(25):2976-2987

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis

Lupo

Tibaldi

Mattè

et al. 2016

Blood

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“…13 In the present study, we used Lyn inhibitors as tools to identify novel players whose function might be altered by the constitutive activity of Lyn and to verify a possible role thereof as therapeutic targets. Importantly, though it is a tyrosine kinase inhibitor, dasatinib is known to cause a drastic decrease in the phosphorylation of specific serine residues of protein kinases that are central to cell survival such as Akt, ERK 1/2, and p38, but not to affect their activity directly.…”

Section: -13mentioning

confidence: 99%

Lyn sustains oncogenic signaling in chronic lymphocytic leukemia by strengthening SET-mediated inhibition of PP2A

Zonta

Pagano

Trentin

et al. 2015

Blood

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Key Points• Cytosolic HSP90-bound Lyn mediates resistance to apoptosis by strengthening PP2A/SET interaction in CLL cells.• FTY720-analogues antagonizing the PP2A/SET interaction and Lyn inhibitors may provide a therapeutic approach of CLL.Aberrant protein kinase activities, and the consequent dramatic increase of Ser/Thr and -Tyr phosphorylation, promote the deregulation of the survival pathways in chronic lymphocytic leukemia (CLL), which is crucial to the pathogenesis and progression of the disease. In this study, we show that the tumor suppressor protein phosphatase 2A (PP2A), one of the major Ser/Thr phosphatases, is in an inhibited form because of the synergistic contribution of 2 events, the interaction with its physiologic inhibitor SET and the phosphorylation of Y307 of the catalytic subunit of PP2A. The latter event is mediated by Lyn, a Src family kinase previously found to be overexpressed, delocalized, and constitutively active in CLL cells. This Lyn/PP2A axis accounts for the persistent high level of phosphorylation of the phosphatase's targets and represents a key connection linking phosphotyrosine-and phosphoserine/threonine-mediated oncogenic signals.The data herein presented show that the disruption of the SET/PP2A complex by a novel FTY720-analog (MP07-66) devoid of immunosuppressive effects leads to the reactivation of PP2A, which in turn triggers apoptosis of CLL cells. When used in combination with SFK inhibitors, the action of MP07-66 is synergistically amplified, providing a new option in the therapeutic strategy for CLL patients. (Blood. 2015;125(24):3747-3755) IntroductionChronic lymphocytic leukemia (CLL), the most common leukemia in the Western world, is characterized by the proliferation of CD5 1 / CD19 1 /CD231 B lymphocytes in lymphoid tissues and bone marrow, which progressively accumulate as mature quiescent cells in the peripheral blood. 1,2 A key role in proliferation and survival of CLL cells is played by microenvironmental factors, which in turn trigger multiple signals mediated by cell surface receptors including CD40, toll-like receptor and B-cell receptor (BCR). [3][4][5] The efforts toward a therapeutic intervention, besides the standard chemo-immunotherapy, have recently focused on hyperactive kinases downstream of the BCR, 6,7 with the development of therapeutically promising inhibitors of these enzymes. [8][9][10] Lyn, for instance, a tyrosine kinase belonging to the Src family kinases (SFKs), has been shown to play a crucial role in the onset and progression of CLL. In CLL cells, Lyn is overexpressed and distributed into 2 pools, one associated beneath the cell surface and the other bound to an aberrant cytosolic complex, which exhibits the constitutive activation responsible for the phosphorylation of a myriad of protein targets in the cytosol and for the resistance of CLL cells to apoptosis. 11-13Because Lyn-targeting drugs, such as dasatinib, 14,15 have yielded disappointing results in managing CLL, [16][17][18][19] we have recently focused on the substrates of...

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“…LYN is also thought to phosphorylate procaspase-8 zymogen, promoting CLL cell survival. It also phosphorylates hematopoietic cell-specific LYN substrate-1 (HS1) that affect cell migration and adhesion [47,48]. Phosphorylation of the ITAMs by LYN subsequently leads to recruitment and activation of spleen tyrosine kinase (SYK), an enzyme essential for coupling BCR activation to distal signal transduction [49][50][51][52].…”

Section: Lyn and Syk Inhibitorsmentioning

confidence: 99%

Management of chronic lymphocytic leukemia (CLL) in the era of B‐cell receptor signal transduction inhibitors

2015

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The treatment of patients with chronic lymphocytic leukemia (CLL), an indolent B-cell lymphoma is in the midst of a transformation. There are a large number of promising new therapeutic agents and cellular therapies being studied which exhibit remarkable activity, favorable toxicity profiles, convenient administration schedules, and treatment options are rapidly expanding. The recent advances in the management of CLL exemplify the value of translational medicine. This review highlights key aspects of Bcell receptor (BCR) signaling in relation to novel inhibitors of the BCR signaling pathway, currently at various stages of preclinical and clinical development.

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Lyn-mediated procaspase 8 dimerization blocks apoptotic signaling in B-cell chronic lymphocytic leukemia

Abstract: Key Points Lyn’s overexpression mediates resistance to apoptosis by promoting phosphorylation and dimerization of procaspase 8 in B-CLL cells.

Cited by 25 publications

References 44 publications

A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis

A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis

Lyn sustains oncogenic signaling in chronic lymphocytic leukemia by strengthening SET-mediated inhibition of PP2A

Management of chronic lymphocytic leukemia (CLL) in the era of B‐cell receptor signal transduction inhibitors

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