Disease relevance of Itga2b

• Mutations in the vWF complex and alphaIIb beta3 have been linked to disorders such as Bernard-Soulier syndrome and Glazmann thrombasthenia respectively [1].
• In order to resolve this controversy, the alpha IIb beta 3-like integrin in murine B16 amelanotic melanoma (B16a) cells was characterized at DNA, RNA, and protein levels [2].
• Moreover, Ab2 does not recognize alpha IIb beta 3-specific antibodies developed by three representative patients with (autoimmune) thrombocytopenic purpura or six representative patients with alloimmune thrombocytopenias, nor does it bind to IgG from any of 13 nonimmunized individuals [3].
• To further define the role of fibrin(ogen) in thrombus formation and stabilization, platelet biology was examined in mice expressing a form of fibrinogen that clots normally but lacks the gamma chain C-terminal binding site for alpha IIb beta 3 (Fg gamma Delta 5) [4].
• Lewis lung carcinoma cells express a plasma membrane receptor (i.e., IRGpIIb/IIIa) which is immunologically and functionally related to the platelet aggregation receptor complex (i.e., GpIIb/IIIa) [5].

High impact information on Itga2b

• The alpha IIb beta 3 integrin binds Arg-Gly-Asp-containing (RGD-containing) ligands in a cation-dependent interaction [6].
• A fourteen amino acid sequence, beta 3 (118-131), and an antibody to it, inhibited ligand binding functions of alpha IIb beta 3, and a 1:1 stoichiometric beta 3 (118-131)-RGD complex was detected by mass spectroscopy [6].
• Paxillin physically associated with alpha4 integrins in Jurkat T cells at high stoichiometry, and joining the alpha4 tail to alphaIIb resulted in a complex of integrin alphaIIbbeta3 with paxillin [7].
• The beta 3 integrin cytoplasmic tyrosine (ICY) motif of alpha IIb beta 3 becomes tyrosine phosphorylated during platelet aggregation, causing Shc and myosin to interact with the beta-integrin cytoplasmic domain [8].
• The alpha integrin GPIIb is a marker of hematopoietic progenitors [9].

Chemical compound and disease context of Itga2b

• We studied 9 patients who developed severe thrombocytopenia (platelets less than 25 x 10(9)/L) within several hours of treatment with the GPIIb/IIIa inhibitors tirofiban (4 patients) and eptifibatide (5 patients) [10].
• Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa [10].
• In vivo antithrombotic efficacy of GPIIb/IIIa receptor antagonists (m7E3, MK-383 and DMP-728) was studied with respect to their ex vivo platelet inhibition in heparinized platelet-rich plasma (hPRP) and citrated platelet-rich plasma (cPRP) using a canine model of carotid artery thrombosis [11].

Biological context of Itga2b

• Conservation of the linkage of the murine Itga2b and Itgb3 loci in mouse chromosome 11 [12].
• CD41 expression defines the onset of primitive and definitive hematopoiesis in the murine embryo [13].
• Using cells derived from mice homozygous for a null allele of gbIIb we show that the absence of GPIIb has no effect on mast cells with respect to a number of measures of cell growth and differentiation [14].
• We set out to investigate expression of GPIIb in other hematopoietic cell lineages and, having detected it on mast cells, aimed to determine what possible role it might perform [14].
• Integrin (alpha)IIb(beta)3 (abbreviated as (alpha)IIb), also known as GPIIb-IIIa or CD41/CD61, is a cell adhesion molecule expressed on cells belonging to the megakaryocytic lineage [15].

Anatomical context of Itga2b

• Some definitive hematopoietic progenitor cells in the fetal liver and bone marrow also express CD41 [13].
• Thus, CD41 expression marks the onset of primitive and definitive hematopoiesis in the murine embryo and persists as a marker of some stem and progenitor cell populations in the fetal liver and adult marrow, suggesting novel roles for this integrin [13].
• We demonstrate that CD41 serves as the earliest marker of primitive erythroid progenitor cells in the embryonic day 7 (E7.0) yolk sac and high-level expression identifies essentially all E8.25 yolk sac definitive hematopoietic progenitors [13].
• These data demonstrate that trafficking of alphaIIb regulates adhesion between trophoblast cells and fibronectin as invasion of the endometrium commences [16].
• In vivo, alphaIIb was highly expressed by invasive trophoblast cells in the ectoplacental cone and trophoblast giant cells of the parietal yolk sac [16].

Associations of Itga2b with chemical compounds

• The platelet glycoprotein IIb (alpha(IIb); CD41) constitutes the alpha subunit of a highly expressed platelet surface integrin protein [13].
• Antibodies known to inhibit fibrinogen binding to GPIIb/IIIa after adenosine diphosphate- and collagen- induced aggregation had very little effect on initial platelet adhesion [17].
• GpIIb/IIIa is the main receptor for initial platelet adhesion to glass and titanium surfaces in contact with whole blood [17].
• alphaIIbbeta3 biogenesis is controlled by engagement of alphaIIb in the calnexin cycle via the N15-linked glycan [18].
• This IgG 2b kappa named 3C7 was specific for the complex of alpha IIb beta3 as demonstrated by flow cytometry, immunoprecipitation, and EDTA chelating [19].

Physical interactions of Itga2b

• In addition, this region of Fn bound specifically to alpha IIb beta 3 on thrombin-stimulated but not resting platelets [20].
• An Ets/Sp1 interaction in the 5'-flanking region of the megakaryocyte-specific alpha IIb gene appears to stabilize Sp1 binding and is essential for expression of this TATA-less gene [21].
• Upon PAC-1 binding to the surface alphaIIb beta3, which is in the active conformation, FAK became dephosphorylated through a process of PKC-dependent phosphatase activation [22].

Regulatory relationships of Itga2b

• Further, thrombopoietin-stimulated alpha IIb-/- mice had a reduced increase in platelet number relative to controls [23].
• Both additional transgenesis using the megakaryocyte specific alphaIIb promoter and targeted transgenesis were used to express the herpes virus thymidine kinase (tk) gene in the megakaryocytic lineage [24].
• In addition, the percent expression of P-selectin and activated GpIIb/IIIa in response to ADP was reproducible in each individual studied on five separate occasions (CV < or = 8%) [25].

Other interactions of Itga2b

• Trafficking of alphaIIb to the apical surface of the trophoblast increased dramatically after blastocysts were exposed to fibronectin, whereas other fibronectin-binding integrins, alpha5beta1 and alphaVbeta3, were resident at the apical surface before ligand exposure [16].
• At 8.25 days post coitus (dpc), CD41 was coexpressed with CD31, CD34, and Flk1 in some intraluminal round cells that appeared to arise from flattened endothelial cells lining yolk sac capillary vessels [26].
• FOG-1 stimulates GATA-1-dependent alphaIIb gene expression in a manner that requires their direct physical interaction [27].
• Binding of bone marrow cells to platelets involves both P-selectin and GPIIb integrin on platelets [28].
• Interestingly, inhibition of Src kinases or Ca2+ release did not inhibit proplatelet formation, indicating that alpha IIb beta3-mediated outside-in signals are not required for this response [23].

Analytical, diagnostic and therapeutic context of Itga2b

• Immunofluorescence results show that initial platelet adhesion to all the surfaces we investigated can be almost completely inhibited (approximately 95%) by clone M148, an antibody against the GPIIb/IIIa complex (integrin alpha(IIb)beta(3); CD41/CD61), but not with other antibodies to the separate parts of the integrin [17].
• The alpha IIb beta 3 protein was identified by Western blotting using subunit-specific antibodies and by immunoprecipitation using complex-specific antibody [2].
• The presence of alpha 5, alpha v, alpha IIb, beta 1, and beta 3 genes in B16a cells was confirmed by Southern analysis. mRNAs for all these integrins except alpha v were detectable by Northern blotting [2].
• The alpha IIb beta 3 integrin was localized intracellularly by immunocytochemistry [2].
• PCR cloning and sequence of the murine GPIIb gene promoter [29].

References