Growth of cells in contact with a surface profoundly affects cellular physiology. In the opportunistic human pathogen Candida albicans, growth on a semi-solid matrix such as agar results in invasive filamentation. This process, in which cells change their morphology to highly elongated filamentous hyphae that grow into the matrix, is reminiscent of the tissue invasion that occurs during human candidiasis. We hypothesized that a plasma membrane protein would sense the presence of matrix and activate a signal transduction cascade, thus promoting invasive filamentation. In this communication, we demonstrate that contact-dependent activation of a MAP kinase, Cek1p, mediated by a plasma membrane protein termed Dfi1p, promotes invasive filamentation. Dfi1p is also required for normal resistance of C. albicans to the cell wall active agents Caspofungin and Congo Red. This novel cell wall sensor is an integral membrane protein that localizes to the plasma membrane, is extensively glycosylated, and can become cross-linked to the cell wall while still anchored in the plasma membrane and retaining its cytoplasmic C-terminus. A GxxxG motif in the transmembrane segment of Dfi1p, similar to ones that promote dimerization in Epidermal Growth Factor Receptor and Glycophorin A, is required for signaling to Cek1p kinase but is dispensable to survive cell wall active drugs. The cytoplasmic facing, membrane juxtaposed domain of Dfi1p binds Ca2+/calmodulin in vitro, and this region is critical for function in vivo. We propose that direct contact of this integral membrane protein with the cell wall enables Dfi1p to activate signaling pathways that promote an appropriate response to a variety of stresses that alter the biophysical properties of the wall.
|Advisor:||Kumamoto, Carol A.|
|Commitee:||Cormack, Brendan, Malamy, Michael, Moore, Claire, Sonenshein, Abraham L.|
|School:||Sackler School of Graduate Biomedical Sciences (Tufts University)|
|School Location:||United States -- Massachusetts|
|Source:||DAI-B 71/03, Dissertation Abstracts International|
|Subjects:||Molecular biology, Microbiology|
|Keywords:||Calmodulin, Candida albicans, Cell wall sensor, Drug resistance, Invasive filamentation, Signal transduction|
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