The membrane glycoprotein Ia-IIa (VLA-2) complex mediates the Mg++-dependent adhesion of platelets to collagen.

Staatz, William D.; Rajpara, Sanjay; Wayner, E A; Carter, W G; Santoro, Samuel A.

doi:10.1083/jcb.108.5.1917

Cited by 397 publications

(214 citation statements)

References 37 publications

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“…GPIa/IIa has been shown to mediate platelet/collagen interactions in platelet and other cell types ( 1,2). To examine whether the amino acid substitution underlying the Br polymorphism affects the function ofGPIa/IIa, we studied platelet adhesion to collagens in the absence and presence ofpurified Bra, Brb human alloantibodies, and mAbs spe- (2), we examined whether the Br-dependent GPIa structural variants affect platelet adhesion to collagen.…”

Section: Resultsmentioning

confidence: 99%

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The human platelet alloantigens Br(a) and Brb are associated with a single amino acid polymorphism on glycoprotein Ia (integrin subunit alpha 2).

Santoso¹,

Kalb²,

Walka³

et al. 1993

J. Clin. Invest.

125

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The human GPIa/Ila complex, also known as integrin a2Bfl, serves as a major receptor for collagen in platelets and other cell types. In addition to its role in platelet adhesion to extracellular matrix, GPIa/IIa is also known to bear the clinically important Br' and Br' alloantigenic determinants, which can result in antibody-mediated platelet destruction. Immunochemical studies showed that the Br antigenic epitopes reside solely on the GP Ia subunit and do not depend on sialic acid residues. To define the polymorphism responsible for the Br alloantigen system platelet RNA PCR technique, was used to amplify GPIa mRNA transcripts. Nucleotide sequence analysis of the amplified platelet GPIa cDNA from Bra/a and Brb/b individuals revealed a single A * G polymorphism at base 1648. MnlI RFLP analysis of cDNA from serologically determined individuals confirmed that this polymorphism segregates with Br phenotype. This single base change results in a substitution of Lys (AAG) in Bra to Glu (GAG) in Brb at amino acid residue 505. In spite of the reversal in charge at this position, however, we found no difference in the ability of Bra and Br' homozygous platelets to adhere to collagens types I, III, or V, nor did antiBra or anti-Br' alloantibodies interfere with platelet adhesion to any of these fibrillar collagens. The identification of the nucleotide substitution that defines the Bra/Brb alloantigen system will now permit both pre-and postnatal diagnosis for Br phenotype. (J. Clin. Invest. 1993. 92:2427-2432

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Section: Resultsmentioning

confidence: 99%

“…In unstimulated platelets, the GPIa/IIa heterodimer mediates Mg2+-dependent platelet adhesion to collagen (2).…”

Section: Introductionmentioning

confidence: 99%

The human platelet alloantigens Br(a) and Brb are associated with a single amino acid polymorphism on glycoprotein Ia (integrin subunit alpha 2).

Santoso¹,

Kalb²,

Walka³

et al. 1993

J. Clin. Invest.

125

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“…The interaction of a2pl with collagen I has been investigated in detail because this reaction is responsible for the adhesion of platelets, the initial step of platelet aggregation (Santoro et al, 1988;Kunicki et al, 1988;Staatz et al, 1989;Takada and Hemler, 1989). A major binding site of collagen I for a2pl has been located within the cyanogenbromide-derived peptide al(I)CB3 (Staatz et al, 1990) and the essential amino acid sequence was determined to be K D G E A (Staatz et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

“…Data represent means of triplicates, deviation below 10%. Marks, 1989;Clyman et al, 1990;Staatz et al, 1989;Ignatius et al, 1990), e.g. the fiber forming collagens I and I11 ( Fig.…”

Section: A L F L and A2b1 Interact With Triple-helical Collagen Ivmentioning

confidence: 99%

Interaction of type IV collagen with the isolated integrins α1β1 and α2β1

Kern

Eble

Golbik

et al. 1993

European Journal of Biochemistry

199

188

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The triple-helical cyanogen-bromide-derived fragment CB3 [IV] of collagen IV, located 100 nm from the N-terminus of the molecule, contains the binding sites for the integrins alp1 and a2pl. To investigate the interaction of these integrins and collagen IV, we performed solid-phase and inhibition assays using as receptor isolated alp1 and a2pl. The ligands used were the binding-site-bearing trimeric peptide CB3 [IV] and its shorter tryptic fragments Fl-F4. Using titration curves, in which the binding of soluble receptors to coated ligands and the binding of soluble ligands to coated receptors were analyzed, the binding sites for alp1 and a2pl were in different but adjacent areas of CB3 [IV]. Triple-helical conformation and distinct primary structures were required for the interaction. Dissociation constants (Kd), for the affinity of integrins for collagen IV, were determined in the 1-nM range in the presence of Mn2+ and Mg". In the absence of Mn2+, the Kd values indicated a 30-60-fold decrease in the affinities, which for a2pl was further reduced by adding Ca". In the presence of Ca2+ and Mg2+ the affinity of collagen IV for alp1 was four-times higher than for a2pl.

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“…[1][2][3][4][5][6][7][8][9][10] In many epithelial malignancies, ␣ 2 ␤ 1 integrin expression is diminished or lost in a manner that correlates with the loss of epithelial differentiation and tumor progression. 2,3,[11][12][13][14] The important role that the ␣ 2 ␤ 1 integrin plays in normal epithelial differentiation has been substantiated by a number of in vitro "gain-offunction" and "loss-of-function" models.…”

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confidence: 99%

Collagen Receptor Control of Epithelial Morphogenesis and Cell Cycle Progression

Zutter

Santoro

et al. 1999

The American Journal of Pathology

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To define the unique contributions of the ␣ subunit cytoplasmic tails of the ␣ 1 ␤ 1 and ␣ 2 ␤ 1 integrin to epithelial differentiation and branching morphogenesis , a variant NMuMG cell line lacking ␣ 1 ␤ 1 and ␣ 2 ␤ 1 integrin expression was stably transfected with the full-length ␣ 2 integrin subunit cDNA (X2C2) , chimeric cDNA consisting of the extracellular and transmembrane domains of the ␣ 2 subunit and the cytoplasmic domain of the ␣ 1 subunit (X2C1) , or ␣ 2 cDNA truncated after the GFFKR sequence (X2C0). The X2C2 and X2C1 transfectants effectively adhered , spread, and formed focal adhesion complexes on type I collagen matrices. The X2C0 transfectants were less adherent to low concentrations of type I collagen , spread less well , and formed poorly defined focal adhesion complexes in comparison to the X2C2 and X2C1 transfectants. The X2C2 and X2C1 transfectants but not the X2C0 transfectants proliferated on collagen substrates. Only the X2C2 transfectants developed elongate branches and tubules in three-dimensional collagen gels and migrated on type I collagen. These findings suggest a unique role for the ␣ 2 integrin cytoplasmic domain in postligand binding events and cooperative interactions with growth factors that mediate epithelial differentiation and branching morphogenesis. Either intact ␣ 1 or ␣ 2 integrin subunit cytoplasmic domain can promote cell cycle progression. (Am J Pathol 1999, 155:927-940)The ␣ 2 ␤ 1 integrin, a collagen/laminin receptor, is expressed at high levels by most normal epithelial cells, and its expression is required for normal epithelial organization, including the formation of branching glands and ducts of the breast. [1][2][3][4][5][6][7][8][9][10] In many epithelial malignancies, ␣ 2 ␤ 1 integrin expression is diminished or lost in a manner that correlates with the loss of epithelial differentiation and tumor progression. 2,3,[11][12][13][14] The important role that the ␣ 2 ␤ 1 integrin plays in normal epithelial differentiation has been substantiated by a number of in vitro "gain-offunction" and "loss-of-function" models. 4,5,15,16 For example, when a full-length ␣ 2 integrin cDNA was introduced into a poorly differentiated, tumorigenic murine breast cancer cell line that expressed no detectable ␣ 2 integrin subunit but high levels of the ␣ 1 integrin subunit, reexpression of the ␣ 2 ␤ 1 integrin resulted in dramatic phenotypic alteration from a fibroblastoid, spindleshaped, non-contact-inhibited cell to an epithelioid, polygonal-shaped, and contact-inhibited cell in culture. 15 Although the adhesion to collagen (mediated by the ␣ 1 ␤ 1 integrin) of the parental and control cells was comparable to the adhesion of the ␣ 2 transfectants, only the ␣ 2 transfectants formed organized structures, including alveolarlike and elongated multilayered duct-like structures in three-dimensional floating collagen gels. These findings suggested that expression of the ␣ 2 ␤ 1 integrin, but not the ␣ 1 ␤ 1 integrin, supported epithelial differentiation and glandular morphogenesis in vi...

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The membrane glycoprotein Ia-IIa (VLA-2) complex mediates the Mg++-dependent adhesion of platelets to collagen.

Cited by 397 publications

References 37 publications

The human platelet alloantigens Br(a) and Brb are associated with a single amino acid polymorphism on glycoprotein Ia (integrin subunit alpha 2).

The human platelet alloantigens Br(a) and Brb are associated with a single amino acid polymorphism on glycoprotein Ia (integrin subunit alpha 2).

Interaction of type IV collagen with the isolated integrins α1β1 and α2β1

Collagen Receptor Control of Epithelial Morphogenesis and Cell Cycle Progression

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