Breaking the integrin hinge. A defined structural constraint regulates integrin signaling.
Integrins are heterodimeric (alpha, beta) cell adhesion receptors. We demonstrate that point mutations in the cytoplasmic domains of both the alpha and beta subunits promote constitutive signaling by the integrin alphaIIbbeta3. By generating charge reversal mutations, we show these "activating" mutations may act by disrupting a potential salt bridge between the membrane-proximal portions of the alpha and beta subunit cytoplasmic domains. Thus, the modulation of specific interactions between the alpha and beta subunit cytoplasmic domains may regulate transmembrane signaling through integrins. In addition, these activating mutations induce dominant alterations in cellular behavior, such as the assembly of the extracellular matrix. Consequently, somatic mutations in integrin cytoplasmic domains could have profound effects in vivo on integrin-dependent functions such as matrix assembly, cell migration, and anchorage-dependent cell growth and survival.
Hughes
P E
PE
Department of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Diaz-Gonzalez
F
F
Leong
L
L
Wu
C
C
McDonald
J A
JA
Shattil
S J
SJ
Ginsberg
M H
MH
D000595:Amino Acid Sequence; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D006224:Cricetinae; D018076:DNA, Complementary; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016023:Integrins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D017354:Point Mutation; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction
D015815:Cell Adhesion Molecules; D018076:DNA, Complementary; D016023:Integrins; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases