Gangliosides, glycosphingolipids of the cell membrane, have been shown in vitro to impact several biologic processes and signaling pathways of normal keratinocytes and the keratinocyte-derived SCC12 cells. These cell functions, proliferation and adhesion, spreading, and migration on a fibronectin matrix, activation of the epidermal growth factor receptor and alpha5beta1integrin and are critical for wound healing. Caveolin-l-containing signaling domains in membranes are sites of coupling of receptors and signaling molecules. We have shown that gangliosides co-immunoprecipitate with caveolin-1, alpha5beta1 and the EGFR, and suggest that gangliosides affect caveolin-1 mediated signaling. We have recently demonstrated that ganglioside GM3 shifts caveolin-1 from detergent-insoluble domains into detergent-soluble domains in proximity with the EGFR. Given the known inhibitory effect of caveolin-1 on the EGFR, this finding suggests that ganglioside may serve as a shuttle molecule to facilitate caveolin-1 interaction with receptors. In this competing application for continuing support we will explore the relationships among gangliosides, caveolin-1, and alpha5beta1 integrin, and the role of these interactions in cell motility. We will investigate: a) the colocalization of gangliosides with caveolin-1, receptors, and signaling molecules by co-immunoprecipitation and immunomicroscopy; b) the dependence of ganglioside function on the intact caveolar domain and/or caveolin-l. We will disrupt caveolar domains with by beta-cyclodextrin and will interfere specifically with caveolin-1 function by introducing antisense oligomers and mutant caveolin-1; c) the effect of caveolin-1 phosphorylation on cell motility; and d) the possibility of direct binding of gangliosides and caveolin-l. The in vivo effect of ganglioside modulation on wound healing will be assessed using a transgenic mouse model of epidermis-specific ganglioside depletion. These studies will provide information about the role of gangliosides in caveolin-1 mediated signaling and may lead to novel therapies for patients with abnormal healing responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR044619-08
Application #
6797303
Study Section
Special Emphasis Panel (ZRG1-GMA-1 (01))
Program Officer
Moshell, Alan N
Project Start
1998-05-01
Project End
2008-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
8
Fiscal Year
2004
Total Cost
$356,960
Indirect Cost
Name
Northwestern University at Chicago
Department
Dermatology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Dam, Duncan Hieu M; Wang, Xiao-Qi; Sheu, Sarah et al. (2017) Ganglioside GM3 Mediates Glucose-Induced Suppression of IGF-1 Receptor-Rac1 Activation to Inhibit Keratinocyte Motility. J Invest Dermatol 137:440-448
Wang, Xiao-Qi; Lee, Sarah; Wilson, Heather et al. (2014) Ganglioside GM3 depletion reverses impaired wound healing in diabetic mice by activating IGF-1 and insulin receptors. J Invest Dermatol 134:1446-1455
Paller, Amy S; van Steensel, Maurice A M; Rodriguez-Martín, Marina et al. (2011) Pathogenesis-based therapy reverses cutaneous abnormalities in an inherited disorder of distal cholesterol metabolism. J Invest Dermatol 131:2242-8
Wang, Xiao-qi; Yan, Qiu; Sun, Ping et al. (2007) Suppression of epidermal growth factor receptor signaling by protein kinase C-alpha activation requires CD82, caveolin-1, and ganglioside. Cancer Res 67:9986-95
Wang, Xiao-Qi; Sun, Ping; Go, Linda et al. (2006) Ganglioside GM3 promotes carcinoma cell proliferation via urokinase plasminogen activator-induced extracellular signal-regulated kinase-independent p70S6 kinase signaling. J Invest Dermatol 126:2687-96
Wang, Xiao-Qi; Sun, Ping; Paller, Amy S (2005) Gangliosides inhibit urokinase-type plasminogen activator (uPA)-dependent squamous carcinoma cell migration by preventing uPA receptor/alphabeta integrin/epidermal growth factor receptor interactions. J Invest Dermatol 124:839-48
Wang, Xiao-Qi; Sun, Ping; Paller, Amy S (2003) Ganglioside GM3 blocks the activation of epidermal growth factor receptor induced by integrin at specific tyrosine sites. J Biol Chem 278:48770-8
Sun, Ping; Wang, Xiao-Qi; Lopatka, Keith et al. (2002) Ganglioside loss promotes survival primarily by activating integrin-linked kinase/Akt without phosphoinositide 3-OH kinase signaling. J Invest Dermatol 119:107-17
Wang, Xiao-Qi; Sun, Ping; Paller, Amy S (2002) Ganglioside induces caveolin-1 redistribution and interaction with the epidermal growth factor receptor. J Biol Chem 277:47028-34
Wang, Xiao-Qi; Sun, Ping; Paller, Amy S (2002) Ganglioside modulation regulates epithelial cell adhesion and spreading via ganglioside-specific effects on signaling. J Biol Chem 277:40410-9

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