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Eukaryotic Cell, March 2007, p. 413-420, Vol. 6, No. 3
1535-9778/07/$08.00+0     doi:10.1128/EC.00213-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Divergence of Protein Kinase A Catalytic Subunits in Cryptococcus neoformans and Cryptococcus gattii Illustrates Evolutionary Reconfiguration of a Signaling Cascade ^,

Julie K. Hicks¹ and Joseph Heitman^1,2,3*

Department of Molecular Genetics and Microbiology,¹ Medicine,² Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710³

Received 6 July 2006/ Accepted 11 December 2006

Gene duplication and divergence via both the loss and gain of gene activities are powerful evolutionary forces underlying the origin of new biological functions. Here a comparative genetics approach was applied to examine the roles of protein kinase A (PKA) catalytic subunits in three closely related varieties or sibling species of the pathogenic fungus genus Cryptococcus. Previous studies revealed that two PKA catalytic subunits, Pka1 and Pka2, control virulence factor production and mating. However, only one of the two plays the predominant physiological role, and this function has been exchanged between Pka1 and Pka2 in strains of the Cryptococcus neoformans var. grubii serotype A lineage compared to divergent C. neoformans var. neoformans serotype D isolates. To understand the basis for this functional plasticity, here the activities of Pka1 and Pka2 were defined in the two varieties and the related sibling species Cryptococcus gattii by gene disruption and characterization, heterologous complementation, and analysis of serotype AD hybrid mutant strains. The findings provide evidence for a shared ancestral role of PKA in governing mating and virulence factor production and indicate that the exchange of catalytic subunit roles is attributable to loss of function. Our studies illustrate the plasticity of signaling networks enabling rapid rewiring during speciation of a clade of common human fungal pathogens.

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* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, 322 CARL Bldg., Duke University Medical Center, Research Dr., Durham, NC 27710. Phone: (919) 684-2824. Fax: (919) 684-5458. E-mail: heitm001{at}duke.edu.

Published ahead of print on 22 December 2006.

Supplemental material for this article may be found at http://ec.asm.org/.

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Eukaryotic Cell, March 2007, p. 413-420, Vol. 6, No. 3
1535-9778/07/$08.00+0     doi:10.1128/EC.00213-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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