Amy Paller, MD, MS
Chair, Department of Dermatology
Walter J. Hamlin Professor of Dermatology
Professor of Pediatrics and Dermatology
Feinberg School of Medicine
Attending Physician, Dermatology
Ann & Robert H. Lurie Children's Hospital of Chicago
Dr. Paller's laboratory is investigating the role of gangliosides in keratinocyte function. Gangliosides are cell-specific sialylated glycosphingolipids of eukaryotic membranes that affect cell-cell recognition, cell-substratum interactions, cell growth regulation, differentiation, and oncogenic transformation. Dr Paller’s laboratory initially defined the ganglioside content of epidermis and cultured keratinocytes, and provided evidence of changes in ganglioside content in disorders of epidermal hyperproliferation, including psoriasis, ichthyoses and squamous and basal cell carcinomas. The laboratory has also shown that modulation of ganglioside content by a variety of biochemical and molecular biological means profoundly affects skin cell function through interaction with receptors and interruption of downstream signaling. For example gangliosides can: (i) down-regulate EGF receptor phosphorylation; (ii) interact with integrins to prevent keratinocyte adhesion, migration and spreading on a fibronectin matrix; (iii) promote apoptosis of keratinocytes and SCC12 cells plated on fibronectin; and (iv) render cells resistant to apoptosis upon depletion. More recently, the laboratory has shown a role of gangliosides as membrane organizers, encouraging or preventing the aggregation of receptors and signaling molecules in lipid rafts that enables signaling to occur. Tetraspanins and caveolin-1 are partners with gangliosides in these effects on signaling. For example, ganglioside GM3 promotes the formation of a membrane-based complex with EGFR, caveolin-1, CD82 and PKC-alpha that promotes EGFR internalization and inhibits signaling. GT1b inhibits cancer cell migration on fibronectin through disruption of a CD151-alpha5beta1 integrin complex that is critical to cell movement on fibronectin. Dr. Paller’s laboratory has more recently turned its attention to the role of GM3 as in intermediate in the TNF-alpha induced resistance to insulin, a problem in obesity and type 2 diabetes. In vitro studies suggest a potent role for ganglioside depletion in promoting wound healing, and wound healing studies in mouse models of both ganglioside depletion (decreased ability to develop resistance to insulin) and diabetes with insulin resistance are in progress to evaluate the role of ganglioside depletion in accelerating re-epithelialization.
Paller, A.S.(2007). Wnt signaling in focal dermal hypoplasia. Nat Genet 39, 820-1.
Wang, X. Q., Yan, Q., Sun, P., Liu, J. W., Go, L., McDaniel, S. M. and Paller, A. S. (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, X. Q. and Paller, A. S. (2006). Lipid rafts: membrane triage centers. J Invest Dermatol 126, 951-3.
Wang, X., Sun, P., Go, L., Koti, V., Fliman, M., and Paller, A.S. (2006). Ganglioside GM3 augments uPA-induced ERK-independent p70S6 kinase activation to stimulate tumor cell proliferation. J Invest Dermatol 126, 2687-96.
Wang, X. Q., Sun, P. and Paller, A. 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.