G protein subunit Galpha13 binds to integrin alphaIIbbeta3 and mediates integrin "outside-in" signaling.
Integrins mediate cell adhesion to the extracellular matrix and transmit signals within the cell that stimulate cell spreading, retraction, migration, and proliferation. The mechanism of integrin outside-in signaling has been unclear. We found that the heterotrimeric guanine nucleotide-binding protein (G protein) Galpha13 directly bound to the integrin beta3 cytoplasmic domain and that Galpha13-integrin interaction was promoted by ligand binding to the integrin alphaIIbbeta3 and by guanosine triphosphate (GTP) loading of Galpha13. Interference of Galpha13 expression or a myristoylated fragment of Galpha13 that inhibited interaction of alphaIIbbeta3 with Galpha13 diminished activation of protein kinase c-Src and stimulated the small guanosine triphosphatase RhoA, consequently inhibiting cell spreading and accelerating cell retraction. We conclude that integrins are noncanonical Galpha13-coupled receptors that provide a mechanism for dynamic regulation of RhoA.
Gong
Haixia
H
Department of Pharmacology, University of Illinois at Chicago, 835 South Wolcott Avenue, Room E403, Chicago, IL 60612, USA.
Shen
Bo
B
Flevaris
Panagiotis
P
Chow
Christina
C
Lam
Stephen C-T
SC
Voyno-Yasenetskaya
Tatyana A
TA
Kozasa
Tohru
T
Du
Xiaoping
X
D000818:Animals; D001665:Binding Sites; D001792:Blood Platelets / Q000502:physiology*; D003018:Clot Retraction; D005340:Fibrinogen / Q000378:metabolism; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D039661:Integrin beta3 / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D010973:Platelet Adhesiveness; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
D039661:Integrin beta3; D008024:Ligands; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C066737:RHOA protein, human; D005340:Fibrinogen; D016392:Proto-Oncogene Proteins pp60(c-src); D044365:GTP-Binding Protein alpha Subunits, G12-G13; D020742:rhoA GTP-Binding Protein