Functional analysis of the cytoplasmic domain of the integrin {alpha}1 subunit in endothelial cells.
Integrin alpha1beta1, the major collagen type IV receptor, is expressed by endothelial cells and plays a role in both physiologic and pathologic angiogenesis. Because the molecular mechanisms whereby this collagen IV receptor mediates endothelial cell functions are poorly understood, truncation and point mutants of the integrin alpha1 subunit cytoplasmic tail (amino acids 1137-1151) were generated and expressed into alpha1-null endothelial cells. We show that alpha1-null endothelial cells expressing the alpha1 subunit, which lacks the entire cytoplasmic tail (mutant alpha1-1136) or expresses all the amino acids up to the highly conserved GFFKR motif (mutant alpha1-1143), have a similar phenotype to parental alpha1-null cells. Pro(1144) and Leu(1145) were shown to be necessary for alpha1beta1-mediated endothelial cell proliferation; Lys(1146) for adhesion, migration, and tubulogenesis and Lys(1147) for tubulogenesis. Integrin alpha1beta1-dependent endothelial cell proliferation is primarily mediated by ERK activation, whereas migration and tubulogenesis require both p38 MAPK and PI3K/Akt activation. Thus, distinct amino acids distal to the GFFKR motif of the alpha1 integrin cytoplasmic tail mediate activation of selective downstream signaling pathways and specific endothelial cell functions.
Abair
Tristin D
TD
Department of Medicine, Division of Nephrology, Vanderbilt University, Nashville, TN, USA.
Bulus
Nada
N
Borza
Corina
C
Sundaramoorthy
Munirathinam
M
Zent
Roy
R
Pozzi
Ambra
A
D020816:Amino Acid Motifs; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D039423:Integrin alpha1 / Q000737:chemistry*; D009154:Mutation; D009389:Neovascularization, Pathologic; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
D039423:Integrin alpha1; D019869:Phosphatidylinositol 3-Kinases