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Papers by Abdel Saci

Biochemical Journal, 2000

Agonist-induced platelet activation triggers ' inside-out ' signalling which activates αIIb-β3, t... more Agonist-induced platelet activation triggers ' inside-out ' signalling which activates αIIb-β3, the most abundant integrin in platelet membranes. The engagement of activated αIIb-β3 integrin by linking fibrinogen is necessary for platelet aggregation, and this induces subsequent outside-in signalling, which enhances platelet activation. Here we studied the involvement of Cbl during αIIb-β3-integrin-mediated signal transduction. During thrombin-induced platelet activation, Cbl was tyrosine phosphorylated, and phosphoinositide 3-kinase (PI 3-kinase) activity measured in Cbl immunoprecipitates was increased. Both Cbl phosphorylation and its association with PI 3-kinase were dependent on αIIb-β3 engagement by linking fibrinogen. The P256 and anti-LIBS6 (ligand-induced binding site 6) antibodies, which activate platelets directly through αIIb-β3, induced

Http Www Theses Fr, 2001

Les plaquettes sanguines sont des cellules differenciees provenant de la fragmentation des megaca... more Les plaquettes sanguines sont des cellules differenciees provenant de la fragmentation des megacaryocytes. Annucleees et donc incapables de proliferer, les plaquettes reagissent aux signaux activateurs par des reponses du type adhesion, agregation et une activite procoagulante. Les reponses plaquettaires different selon l'agoniste et la voie de transduction du signal activee. L'action d'un agoniste sur les plaquettes transmet un signal, dit inside-out, activateur de l'integrine αIIb-β3. En consequence, αIIb-β3 activee fixe le fibrinogene et permet la transmission d'un signal activateur secondaire, dit outside-in. La premiere partie de ces travaux a consiste en l'etude de l'implication de la proteine adaptatrice Cbl et de la lipide kinase, PI 3-K, dans les voies de signalisation mediees par (i) le recepteur du domaine Fc des IgG (FcγRIIa), (ii) l'integrine αIIb-β3 (outside-in) et le recepteur de la thrombine. Nous avons montre que Cbl est fortement phosphorylee sur tyrosine au cours de l'activation de la voie de (FcγRIIa), alors qu'elle ne l'est que faiblement a la thrombine. . .

Journal of Biological Chemistry, 1999

The platelet receptor for the Fc domain of IgGs (Fc␥RIIa) triggers intracellular signaling throug... more The platelet receptor for the Fc domain of IgGs (Fc␥RIIa) triggers intracellular signaling through protein tyrosine phosphorylations leading to platelet aggregation. In this study, we focused on the adaptor protein p120 cbl (Cbl), which became tyrosine-phosphorylated after platelet activation induced by antibodies. Cbl phosphorylation was dependent on Fc receptor engagement. An association of Cbl with the p85 subunit of phosphatidylinositol 3-kinase (PI 3-K) occurred in parallel with Cbl tyrosine phosphorylation. We showed by in vitro experiments that Cbl/p85 association was mediated by the Src homology 3 domain of p85/PI 3-K and the prolinerich region of Cbl. Inhibition of PI 3-K activity by wortmannin led to the blockade of both platelet aggregation and serotonin release mediated by Fc␥RIIa engagement, whereas it only partly inhibited those induced by thrombin. Thus, PI 3-K may play a crucial role in the initiation of platelet responses after Fc␥RIIa engagement. Our results suggest that Cbl is involved in platelet signal transduction by the recruitment of PI 3-K to the Fc␥RIIa pathway, possibly by increasing PI 3-K activity.

Immunity, 2003

and substrate (Willars et al., 1998). These observations sug-2 Department of Medicine gest that s... more and substrate (Willars et al., 1998). These observations sug-2 Department of Medicine gest that stimulation of PtdIns-4,5-P 2 synthesis could Beth Israel Deaconess Medical Center and be an essential regulatory step to sustain the activation Harvard Medical School of PI3K and PLC, yet this possibility has never been in-Boston, Massachusetts 02215 vestigated. 3 The Molecular Biology Institute PtdIns-4,5-P 2 is synthesized by the phosphorylation University of California, Los Angeles of PtdIns-4-P at the D-5 position of the inositol ring by Los Angeles, California 90095 phosphatidylinositol-4-phosphate 5-kinases (PIP5Ks). 4 Department of Pediatrics and There are three isoforms of PIP5Ks, ␣, ␤ and ␥, which 5 Department of Immunology are all widely expressed (Carvajal et al., 1996; Ishihara

Biochemical Journal, 2002

The adaptor protein Grb2 (growth factor receptor-bound protein 2) is involved in cell proliferati... more The adaptor protein Grb2 (growth factor receptor-bound protein 2) is involved in cell proliferation via the Ras signalling pathway. In order to study the role of Grb2 in blood platelet responses, we used a peptide containing two proline-rich sequences derived from Sos (peptidimer), which binds to Grb2-Src homology 3 domain (SH3) with a high affinity, and hence inhibits Grb2-SH3mediated protein interactions. Platelet aggregation and 5hydroxytryptamine (serotonin) release measured in the presence of the peptidimer were : (i) significantly decreased when induced by thrombin; and (ii) potentiated when induced by the engagement of the Fc receptor. In thrombin-activated platelets, the Grb2-SH2 domain formed an association with the β3 subunit of the αIIb-β3 integrin (GPIIb-IIIa), Shc, Syk, Src and SHP1 (SH2-containing phosphotyrosine phosphatase 1), whereas these associations did not occur after the engagement of the receptor for the Fc domain of IgG (FcγRIIa) or in resting platelets. Grb2-SH3 domains formed an association with the proline-rich

Blood, 2003

Shear-induced platelet aggregation (SIPA) involves the sequential interaction of von Willebrand f... more Shear-induced platelet aggregation (SIPA) involves the sequential interaction of von Willebrand factor (VWF) with both glycoprotein Ib (GPIb) and αIIbβ3 receptors. Type 2B recombinant VWF (2B-rVWF), characterized by an increased affinity for GPIb, induces strong SIPA at a high shear rate (4000 s–1). Despite the increased affinity of 2B-rVWF for GPIb, patients with type 2B von Willebrand disease have a paradoxical bleeding disorder, which is not well understood. The purpose of this study was to determine if SIPA induced by 2B-rVWF was associated with αIIbβ3-dependent platelet activation. To this end, we have addressed the influence of 2B-rVWF (Val553Met substitution) on SIPA-dependent variations of tyrosine protein phosphorylation (P-Tyr) and the effect of αIIbβ3 blockers. At a high shear rate, 2B-rVWF induced a strong SIPA, as shown by a 92.7% ± 0.4% disappearance of single platelets (DSP) after 4.5 minutes. In these conditions, increased P-Tyr of proteins migrating at positions 64 ...

Annales de Dermatologie et de Vénéréologie, 2019

Déclaration de liens d'intérêts Les auteurs déclarent ne pas avoir de liens d'intérêts. ଝ Les ill... more Déclaration de liens d'intérêts Les auteurs déclarent ne pas avoir de liens d'intérêts. ଝ Les illustrations et tableaux liés aux abstracts sont disponibles à l'adresse suivante :

Molecular Cell, 2005

Abdelhafid Saci and Christopher L. Carpenter* required for immune receptor signaling, suggesting ... more Abdelhafid Saci and Christopher L. Carpenter* required for immune receptor signaling, suggesting that Division of Signal Transduction signals dependent on Rho GTPases are also necessary. Department of Medicine Splenic B cells from mice lacking expression of either Beth Israel Deaconess Medical Center Vav1 or Vav2 have subtle defects in development and Boston, Massachusetts 02115 BCR signaling. B cells from mice lacking expression of both Vav1 and Vav2, or all three Vav family members, however, have profound defects in B cell development Summary and BCR signaling, including absence of BCR-stimulated calcium flux (Zhang et al., 1995; Tedford et al., The RhoA GTPase controls many cellular functions, 2001; Doody et al., 2001; Fujikawa et al., 2003). The including gene transcription and actin polymerization. function of Rho family members in B cells is not under-Several lines of evidence suggest that Rho GTPases stood, nor is it even known whether RhoA is required are required for B cell receptor (BCR) signaling, but for signaling in B cells. whether RhoA is necessary has not been investigated. Signals generated by the BCR are crucial for B cell Here, we show that RhoA is activated, downstream of survival, proliferation, development, differentiation, and PI3K, in response to BCR stimulation and is important apoptosis (Kurosaki et al., 2000; Turner, 2002). The sigfor BCR-dependent calcium flux and cell proliferation. naling subunit of the BCR is composed of immunoglobu-A RhoA dominant-negative mutant strongly inhibited lin and CD79a (Ig␣) and CD79b (Ig␤) polypeptides, which BCR-dependent calcium mobilization. The RhoA-specontain immunoreceptor tyrosine-based activation mocific inhibitor, C3 toxin, inhibited both BCR-dependent tifs (ITAMs). Once tyrosine phosphorylated, these motifs calcium flux and cell proliferation. RhoA is important bind to the protein tyrosine kinase Syk, leading to its for BCR-dependent synthesis of IP 3 by PLC␥2, but is phosphorylation and activation. Subsequently, Btk, Vav not required for tyrosine phosphorylation of PLC␥2. proteins, and phosphoinositide 3-kinase (PI3K) are acti-BCR-dependent synthesis of phosphatidylinositolvated, resulting in PLC␥2-dependent IP 3 production and 4,5-bisphosphate (PtdIns-4,5-P 2) is inhibited in the aban increase in cytoplasmic calcium (Fruman et al., 2000). sence of RhoA function. Providing exogenous PtdIns-Although many of the components of BCR-regulated 4,5-P 2 restores BCR-dependent calcium flux in cells pathways have been identified, there still are significant lacking functional RhoA. Our findings support a funcgaps in our understanding. The functions of PI3K and tion for RhoA in BCR-dependent PtdIns-4,5-P 2 synthethe Vav proteins required for BCR signaling are not essis, PLC␥2 activation, calcium mobilization, and cell tablished, and the regulation of PLC␥2 is incompletely proliferation. understood. Here, we investigated the role of RhoA in BCR signal-Introduction ing and provide evidence for its involvement in the regulation of BCR-dependent calcium flux and proliferation. RhoA is a member of the Rho family of small GTPases RhoA is activated upon BCR engagement, downstream and regulates several cellular functions, including actin of PI3K activation, in both A20 and primary B cells. We rearrangement, polarity, transcription, and cell cycle used both a dominant-negative (DN) mutant of RhoA progression. RhoA, like other GTPases, transmits sigand a RhoA-specific inhibitor, C3 toxin, to show that nals by binding to effector proteins. GTPases undergo RhoA is important for BCR-dependent calcium flux. IP 3 a conformational change when bound to GTP, and most production is inhibited by DN RhoA mutant, but PLC␥2 effectors associate with this form. Binding to GTPases tyrosine phosphorylation is unaffected. Inhibition of RhoA results in effector activation and/or specific localization. function blocks PtdIns-4,5-P 2 , PA, and PtdIns-4-P syn-GTP loading is catalyzed by guanine nucleotide exthesis. RhoA associates with phosphatidylinositol-4change factors (GEFs). GTPase-activating proteins phosphate 5-kinase and phosphatidylinositol 4-kinase, (GAPs) accelerate hydrolysis of GTP and the return to the enzymes that synthesize PtdIns-4,5-P 2 and PtdInsthe inactive GDP-bound state (Schmidt and Hall, 2002). 4-P, respectively. Providing B cells with exogenous Lymphocytes require Rho family members for normal PtdIns-4,5-P 2 rescued BCR-dependent calcium flux in development and function. Expression of RhoA mutants cells expressing the N19RhoA mutant, confirming the or the RhoA-specific inhibitor, C3 toxin, as transgenes requirement for substrate provision for PLC␥2 activity. in T cells affects T cell development and survival by an We showed that RhoA is necessary for BCR-mediated unknown mechanism (Henning et al., 1997; Costello et cell proliferation by using C3 toxin in primary B cells. al., 2000; Corre et al., 2001). B cell development and These data support a function for RhoA in the regulation BCR signaling leading to proliferation and survival reof B cell receptor signaling. quire Rac1 and Rac2 (Walmsley et al., 2003). Lymphocytes from mice lacking RhoG, however, develop Results normally, despite a slight increase in some immune responses (Vigorito et al., 2004). Vav proteins are GEFs RhoA Is Activated upon B Cell for Rho family GTPases (Crespo et al., 1997; Han et al., Receptor Engagement Since activation of RhoA is a prerequisite for its participation in BCR-dependent signaling, we initially investi

Annals of Oncology, 2019

Background The phase III study CheckMate 238 demonstrated improved relapse-free survival (RFS) wi... more Background The phase III study CheckMate 238 demonstrated improved relapse-free survival (RFS) with NIVO 3 mg/kg vs IPI 10 mg/kg in patients (pts) with resected stage III/IV melanoma. Sustained efficacy benefit at 24 mo of follow-up with NIVO vs IPI was previously reported. Here we present a 36mo analysis of efficacy and biomarker data from this study. Methods Pts aged ≥ 15 y with completely resected stage IIIB/C or IV melanoma were randomized 1:1 to receive NIVO (3 mg/kg Q2W; N = 453) or IPI (10 mg/kg Q3W for 4 doses; Q12W thereafter; N = 453) for ≤ 1 y or until disease recurrence/unacceptable toxicity. RFS was the primary endpoint; exploratory endpoints included distant metastases-free survival (DMFS) in pts with stage III disease and potential biomarkers of efficacy. Results With 36 mo of follow-up, NIVO continued to demonstrate superior RFS vs IPI (HR, 0.68; P

Genome-wide copy number analyses of human cancers identified a frequent 5p13 amplification in mul... more Genome-wide copy number analyses of human cancers identified a frequent 5p13 amplification in multiple solid tumor types, including lung (56%), ovarian (38%), breast (32%), prostate (37%) and melanoma (32%). Integrative analysis of the region identifies a Golgi protein, GOLPH3, as a candidate targeted for amplification. Gain- and loss-of-function studies in vitro and in vivo validated GOLPH3 as a potent oncogene. Physically, GOLPH3 localizes to the trans-Golgi network and interacts with components of the retromer complex, which in yeast has been linked to TOR signaling. Mechanistically, GOLPH3 regulates cell size, enhances growth factor-induced mTOR signaling in human cancer cells and alters response to mTOR inhibitor in vivo. Thus, reinforcing genomic and genetic, biological, functional and biochemical data in yeast and humans Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full...

488Background: Immune checkpoint therapy can produce durable anti-tumor responses in metastatic u... more 488Background: Immune checkpoint therapy can produce durable anti-tumor responses in metastatic urothelial carcinoma (mUCC); however, the responses are not universal. Despite multiple approvals of ...

Cancer Immunology Research

Science Translational Medicine

Immune checkpoint therapy (ICT) can produce durable antitumor responses in metastatic urothelial ... more Immune checkpoint therapy (ICT) can produce durable antitumor responses in metastatic urothelial carcinoma (mUCC); however, the responses are not universal. Despite multiple approvals of ICT in mUCC, we lack predictive biomarkers to guide patient selection. The identification of biomarkers may require interrogation of both the tumor mutational status and the immune microenvironment. Through multi-platform immuno-genomic analyses of baseline tumor tissues, we identified the mutation of AT-rich interactive domain-containing protein 1A (ARID1A) in tumor cells and expression of immune cytokine CXCL13 in the baseline tumor tissues as two predictors of clinical responses in a discovery cohort (n = 31). Further, reverse translational studies revealed that CXCL13−/− tumor-bearing mice were resistant to ICT, whereas ARID1A knockdown enhanced sensitivity to ICT in a murine model of bladder cancer. Next, we tested the clinical relevance of ARID1A mutation and baseline CXCL13 expression in two ...