Modulation of Leukocyte Adhesion by P-selectin/PSGL-1 Signaling Leukocyte recruitment entails a cascade of cellular events, including rolling and firm adhesion of responding cells. P-selectin (CD62P), P-selectin glycoprotein ligand-1 (PSGL-1, CD162) and beta2-integrins are endothelial and leukocyte cell adhesion molecules essential for innate immunity and inflammation. The interaction of P-selectin with PSGL-1 mediates leukocyte rolling, during which they become sufficiently activated in situ by locally released or displayed cytokines and chemoattractants for beta2-integrin-mediated firm adhesion. However, the mechanisms for feedback regulation of P-selectin adhesion activity and P- selectin-induced beta2-integrin activation remain undetermined. Nef-associated factor 1 (Nafl) is an endogenous inhibitor for NF-kappaB activation. Serum amyloid P component (SAP) is an acute phase protein synthesized and secreted rapidly by hepatocytes in response to various inflammatory mediators. In the preliminary studies, we found that Naf1 formed a stable complex with the cytoplasmic tail of PSGL-1. Engagement of PSGL-1 by P-selectin phosphorylated the Y552PPM motif of Naf1 for recruiting p85 subunit of phosphatidylinositol-3 kinase (PI3K) and triggering the signaling cascade that culminated in activation of alphaMbeta2 (CD11bCD18, Mac-1). In addition, we observed that SAP interacted with P-selectin and acted as an endogenous inhibitor of PSGL-1 for P-selectin recognition. In this grant application, we propose 1) to define the functional importance of P-selectin-induced activation of alphaMbeta2;2) to determine the biological significance of the PSGL-1-Naf1-p85 signaling pathway for modulation of alphaMbeta2 activity;and 3) to explore the regulation of P-selectin adhesion activity by SAP. Overall, this study will not only enhance our understanding of molecular mechanisms that precisely determine leukocyte fates in the multi- step paradigm of leukocyte recruitment, but also discover novel therapeutic targets for prevention and treatment of inflammatory disorders.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Erythrocyte and Leukocyte Biology Study Section (ELB)
Program Officer
Minnicozzi, Michael
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Dentistry
Ann Arbor
United States
Zip Code
Ji, Zhe; Ke, Zun-Ji; Geng, Jian-Guo (2012) SAP suppresses the development of experimental autoimmune encephalomyelitis in C57BL/6 mice. Immunol Cell Biol 90:388-95
Feng, Lifeng; Wang, Jin-Tao; Jin, Hongchuan et al. (2011) SH3KBP1-binding protein 1 prevents epidermal growth factor receptor degradation by the interruption of c-Cbl-CIN85 complex. Cell Biochem Funct 29:589-96
Han, Hai-xiong; Geng, Jian-guo (2011) Over-expression of Slit2 induces vessel formation and changes blood vessel permeability in mouse brain. Acta Pharmacol Sin 32:1327-36
Wang, L-J; Zhou, X; Wang, W et al. (2011) Andrographolide inhibits oral squamous cell carcinogenesis through NF-?B inactivation. J Dent Res 90:1246-52
Yang, Xiao-Mei; Han, Hai-Xiong; Sui, Fei et al. (2010) Slit-Robo signaling mediates lymphangiogenesis and promotes tumor lymphatic metastasis. Biochem Biophys Res Commun 396:571-7
Ye, Bu-Qing; Geng, Zhen H; Ma, Li et al. (2010) Slit2 regulates attractive eosinophil and repulsive neutrophil chemotaxis through differential srGAP1 expression during lung inflammation. J Immunol 185:6294-305
Li, Yi-Dan; Ye, Bu-Qing; Zheng, Sheng-Xi et al. (2009) NF-kappaB transcription factor p50 critically regulates tissue factor in deep vein thrombosis. J Biol Chem 284:4473-83
Wang, Li-Jing; Zhao, Yuan; Han, Bing et al. (2008) Targeting Slit-Roundabout signaling inhibits tumor angiogenesis in chemical-induced squamous cell carcinogenesis. Cancer Sci 99:510-7
Wang, Hai-Bo; Wang, Jin-Tao; Zhang, Lei et al. (2007) P-selectin primes leukocyte integrin activation during inflammation. Nat Immunol 8:882-92