XIAP is essential for shear stress-enhanced Tyr-576 phosphorylation of FAK.
In endothelial cells, X-chromosome linked inhibitor of apoptosis protein (XIAP) regulates cell survival, migration and adhesion. We have recently found that XIAP recruits focal adhesion kinase (FAK) into integrin-associated focal adhesions, controlling cell migration. However, little is understood about the molecular mechanisms by which FAK modulation is controlled by XIAP. In this study, we show that XIAP modulates FAK activity through the control of FAK phosphorylation. In bovine aortic endothelial cells (BAEC), phosphorylation of Tyr-576 in FAK is elevated by laminar shear stress. This elevated phosphorylation appears to be responsible for shear stress-stimulated ERK activation. We found that XIAP knockdown reduces shear stress-enhanced phosphorylation of Tyr-576 and induces shear stress-triggered translocation of FAK into nucleus. Nuclear translocation of FAK reduces contact between FAK and Src, a kinase which phosphorylates Tyr-576. This spatial segregation of FAK from Src decreases Tyr-576 phosphorylation and thus shear-stimulated ERK activation. Taken together, our results demonstrate that XIAP plays a key role in shear stress-stimulated ERK activation by maintaining the Src-accessible location of FAK.
Ahn
Sunyoung
S
Department of Molecular Biology & Institute of Nanosensor and Biotechnology, BK21 Graduate Program for RNA Biology, Dankook Univiersity, 126, Jukjeon-dong, Suji-gu, Yongin-si, Gyeonggi-do, 448-701, Republic of Korea.
Park
Heonyong
H
D000818:Animals; D002417:Cattle; D004730:Endothelium, Vascular / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D033081:Shear Strength; D013314:Stress, Mechanical; D014443:Tyrosine / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
D034741:RNA, Small Interfering; D051636:X-Linked Inhibitor of Apoptosis Protein; D014443:Tyrosine; D051417:Focal Adhesion Kinase 1; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases