Research in our lab investigates signal transduction pathways that regulate growth, survival and metabolism of mammalian cells. Genetic alterations in numerous signaling pathways contribute to human pathologies such as cancer and diabetes. Combinatorial drug therapies designed to target multiple signaling pathways hold promise in treating human disease, but this critically depends upon an understanding of the interactions of signaling molecules.
Many oncogenes activate signaling pathways originating from receptor tyrosine kinases at the cell surface. One major pathway turned on during neoplasia is the phosphoinositide 3-kinase (PI3K) pathway. PI3K is a lipid kinase that regulates the subcellular distribution of other signaling proteins, and in particular members of the AGC kinase family. With over 60 family members, the AGC kinase family regulates a host of cellular functions including proliferation, survival, shape and mobility – typically the arsenal of tools a cell needs to successfully become a malignant tumor. Several tumor suppressors that are often disabled in human cancer normally operate to suppress PI3K signaling to various AGC kinases.
One member of the AGC kinase family of particular interest is PDK1. PDK1 is a master switch regulating the activity of other kinases that are often dysregulated during neoplasia. We are interested in the mechanism of PDK1 regulation, including how it phosphorylates its various substrates, its subcellular shuttling, and its interaction with PI3K.
Methodologies used in the lab include molecular biology, cell biology, microscopy, tissue culture, gene expression, protein purification and biochemistry.
Couzens AL, Gill RM, Scheid MP. Characterization of a modified ROCK2 protein that allows use of N6-ATP analogs for the identification of novel substrates. BMC Biotechnol. 2014 Jan 9;14:2.
Matitau AE, Gabor TV, Gill RM, Scheid MP. MEKK2 kinase association with 14-3-3 protein regulates activation of c-Jun N-terminal kinase. J Biol Chem. 2013 Sep 27;288(39):28293-302.
Gill RM, Gabor TV, Couzens AL, Scheid MP. The MYC-associated protein CDCA7 is phosphorylated by AKT to regulate MYC-dependent apoptosis and transformation. Mol Cell Biol. 2013 Feb;33(3):498-513.
Couzens AL, Saridakis V, Scheid MP. The hydrophobic motif of ROCK2 requires association with the N-terminal extension for kinase activity. Biochem J. 2009 Apr 1;419(1):141-8.
Scheid MP, Huber M, Damen JE, Hughes M, Kang V, Neilsen P, Prestwich GD, Krystal G, Duronio V (2002) Phosphatidylinositol (3,4,5)P3 is essential but not sufficient for protein kinase B (PKB) activation. J Biol Chem 277:9027-9035.