The mechanisms by which stress and growth control signals are transmitted from the cell surface to their ultimate intracellular targets is central to understanding how cells respond to changes in their environment. We study the signal transduction pathways associated with the maintenance of cell wall integrity in yeast. The major signaling pathway responsible for monitoring the state of the cell wall during growth and morphogenesis is mediated by a family of cell surface stress sensors, a small G-protein (Rho1), protein kinase C (Pkc1), a MAP kinase cascade, and at least one transcription factor (Rlm1). Mutants in this pathway construct weak cell walls that cause them to lyse, a behavior that can be exploited for the development of drugs with potent antifungal activity.

A second area of investigation is the role of Ras signaling in filamentous/invasive growth. Ras is a small G-protein that is implicated in the development of 30% of tumors in humans. In pathogenic fungi, a dimorphic shift from a yeast form to an invasive hyphal form is associated with pathogenesis. In yeast, Ras is a controlling element of a similar dimorphic shift. We have recently identified a novel target of yeast Ras signaling, that is important for this shift. The target is an enzyme complex at the endoplasmic reticulum that is involved in the maturation of cell wall proteins. This work has implications both for treating fungal infections and for understanding the mechanisms of Ras-involved tumorigenesis.

Biochemistry and molecular biology, yeast, stress and growth control signals, signal transduction pathways

Newman, H.A., Romeo, M.J., Lewis, S.E., Yan, B.C., Orlean, P. and Levin, D.E. (2005) Gpi19, the Saccharomyces cerevisiae homologue of mammalian PIG-P, is a subunit of the initial enzyme for glycosylphosphatidylinositol anchor biosynthesis. Euk. Cell 4:1801-1807.

Levin, D.E. (2005). Cell wall integrity signaling in Saccharomyces cerevisiae. Micro. Mol. Biol. Rev. 69:262-291.

Vay, H.A., Philip, B., and Levin, D.E. (2004). Mutational analysis of the cytoplasmic domain of the Wsc1 cell wall stress sensor. Microbiol. 150:3281-3288.

Sobering, A.K., Watanabe, R., Romeo, M.J., Yan, B.C., Specht, C.A., Orlean, P., Riezman, H., and Levin, D.E. (2004). Yeast Ras regulates the complex that catalyzes the first step in GPI-anchor biosynthesis at the ER. Cell 117:637-648.

Sobering, A.K., Romeo, M.J., Vay, H.A., and Levin, D.E. (2003). A novel Ras inhibitor, Eri1, engages yeast Ras at the endoplasmic reticulum. Mol. & Cell. Biol. 23(14):4983-4990.

Romeo, M.J., Angus-Hill, M.L., Sobering, A.K., Kamada, Y., Cairns, B.R., and Levin, D.E. (2002). HTL1 encodes a novel factor that interacts with the RSC chromatin remodeling complex in Saccharomyces cerevisiae. Mol. & Cell. Biol. 22(23):8165-8174.

Jung, U.S., Sobering, A.K., Romeo, M.J., and Levin, D.E. (2002). Regulation of the yeast Rlm1 transcription factor by the Mpk1 cell wall integrity MAP kinase. Mol. Microbiology. 46(3):781-789.

Sobering A.K., Jung, U.S., Lee, K.S., and Levin, D.E. (2002). Yeast Rpi1 is a putative transcriptional regulator that contributes to preparation for stationary phase. Euk. Cell 1(1):56-65.

Philip, B., and Levin, D.E. (2001). Wsc1 and Mid2 are cell surface sensors for cell wall integrity signaling that act through Rom2, a guanine nucleotide exchange factor for Rho1. Mol. & Cell. Biol. 21(1):271-280.

Rajavel, M., Philip, B., Buehrer, B.M., Errede, B. and Levin, D.E. (1999). Mid2 is a putative sensor for cell integrity signaling in Saccharomyces cerevisiae. Mol. Cell. Biol. 19:3969-76.

Jung, U.S., and Levin, D.E. (1999). Genome-wide analysis of gene expression regulated by the yeast cell wall integrity signalling pathway. Mol. Microbiology 34:1049-57.