Missense mutations in the beta(3) subunit have a different impact on the expression and function between alpha(IIb)beta(3) and alpha(v)beta(3).
Alpha(IIb)beta(3) and alpha(v)beta(3) belong to the beta(3) integrin subfamily. Although the beta(3) subunit is a key regulator for the biosynthesis of beta(3) integrins, it remains obscure whether missense mutations in beta(3) may induce the same defects in both alpha(IIb)beta(3) and alpha(v)beta(3). In this study, it is revealed that thrombasthenic platelets with a His280Pro mutation in beta(3), which is prevalent in Japanese patients with Glanzmann thrombasthenia, did contain significant amounts of alpha(v)beta(3) (about 50% of control) using sensitive enzyme-linked immunosorbent assay. Expression studies showed that the His280Probeta(3) mutation impaired alpha(IIb)beta(3) expression but not alpha(v)beta(3) expression in 293 cells. To extend these findings, the effects of several beta(3) missense mutations leading to an impaired alpha(IIb)beta(3) expression on alpha(v)beta(3) function as well as expression was examined: Leu117Trp, Ser162Leu, Arg216Gln, Cys374Tyr, and a newly created Arg216Gln/Leu292Ser mutation. Leu117Trp and Cys374Tyr beta(3) mutations did impair alpha(v)beta(3) expression, while Ser162Leu, Arg216Gln, and Arg216Gln/Leu292Ser mutations did not. With regard to ligand binding function, Ser162Leu mutation induced especially distinct effects between 2 beta(3) integrins: it markedly impaired ligand binding to alpha(IIb)beta(3) but not to alpha(v)beta(3) at all. These data clearly demonstrate that the biosynthesis and the ligand binding function of alpha(IIb)beta(3) and those of alpha(v)beta(3) are regulated in part by different mechanisms. Present data would be a clue to elucidate the regulatory mechanism of expression and function of beta(3) integrins.
Tadokoro
Seiji
S
Department of Internal Medicine and Molecular Science, Graduate School of Medicine B5, Osaka University, 2-2 Yamadaoka, Suita Osaka 565-0871, Japan.
Tomiyama
Yoshiaki
Y
Honda
Shigenori
S
Kashiwagi
Hirokazu
H
Kosugi
Satoru
S
Shiraga
Masamichi
M
Kiyoi
Teruo
T
Kurata
Yoshiyuki
Y
Matsuzawa
Yuji
Y
D000328:Adult; D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D001792:Blood Platelets / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004252:DNA Mutational Analysis; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D039661:Integrin beta3; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense / Q000235:genetics; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics* / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D019030:Receptors, Vitronectin / Q000235:genetics* / Q000378:metabolism; D013915:Thrombasthenia / Q000097:blood / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D015703:Antigens, CD; D039661:Integrin beta3; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins; D019030:Receptors, Vitronectin; D005340:Fibrinogen