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Blood, 15 October 2008, Vol. 112, No. 8, pp. 3242-3254.
Prepublished online as a Blood First Edition Paper on July 22, 2008; DOI 10.1182/blood-2007-12-126433.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Functional analysis of the cytoplasmic domain of the integrin  1 subunit in endothelial cells
Tristin D. Abair1,2,
Nada Bulus1,
Corina Borza1,
Munirathinam Sundaramoorthy1,
Roy Zent14, and
Ambra Pozzi1,2,4
Departments of1 Medicine (Division of Nephrology),
2 Cancer Biology, and
3 Cell and Developmental Biology, Vanderbilt University, Nashville, TN; and
4 Department of Medicine, Veterans Affairs Hospital, Nashville, TN
Integrin  1β1, 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 1 subunit cytoplasmic tail (amino acids 1137-1151) were generated and expressed into 1-null endothelial cells. We show that 1-null endothelial cells expressing the 1 subunit, which lacks the entire cytoplasmic tail (mutant 1-1136) or expresses all the amino acids up to the highly conserved GFFKR motif (mutant 1-1143), have a similar phenotype to parental 1-null cells. Pro1144 and Leu1145 were shown to be necessary for 1β1-mediated endothelial cell proliferation; Lys1146 for adhesion, migration, and tubulogenesis and Lys1147 for tubulogenesis. Integrin 1β1–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 1 integrin cytoplasmic tail mediate activation of selective downstream signaling pathways and specific endothelial cell functions.
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