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Eukaryotic Cell, November 2008, p. 1880-1887, Vol. 7, No. 11
1535-9778/08/$08.00+0     doi:10.1128/EC.00222-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Synthetic Genetic Network around PKC1 Identifies Novel Modulators and Components of Protein Kinase C Signaling in Saccharomyces cerevisiae{triangledown}

Sue A. Krause,1 Hong Xu,2,{dagger} and Joseph V. Gray1*

Molecular Genetics and Integrative & Systems Biology, Faculty of Biomedical and Life Sciences, University of Glasgow, Anderson College Complex, 56 Dumbarton Road, Glasgow G11 6NU, United Kingdom,1 Banting and Best Department of Medical Research, University of Toronto, 112 College Street, Toronto, Ontario M5G 1L6, Canada2

Received 7 July 2008/ Accepted 9 September 2008

Budding yeast Saccharomyces cerevisiae contains one protein kinase C (PKC) isozyme encoded by the essential gene PKC1. Pkc1 is activated by the small GTPase Rho1 and plays a central role in the cell wall integrity (CWI) signaling pathway. This pathway acts primarily to remodel the cell surface throughout the normal life cycle and upon various environmental stresses. The pathway is heavily branched, with multiple nonessential branches feeding into and out of the central essential Rho1-Pkc1 module. In an attempt to identify novel components and modifiers of CWI signaling, we determined the synthetic lethal genetic network around PKC1 by using dominant-negative synthetic genetic array analysis. The resulting mutants are hypersensitive to lowered Pkc1 activity. The corresponding 21 nonessential genes are closely related to CWI function: 14 behave in a chemical-genetic epistasis test as acting in the pathway, and 6 of these genes encode known components. Twelve of the 21 null mutants display elevated CWI reporter activity, consistent with the idea that the pathway is activated by and compensates for loss of the gene products. Four of the 21 mutants display low CWI reporter activity, consistent with the idea that the pathway is compromised in these mutants. One of the latter group of mutants lacks Ack1(Ydl203c), an uncharacterized SEL-1 domain-containing protein that we find modulates pathway activity. Epistasis analysis places Ack1 upstream of Pkc1 in the CWI pathway and dependent on the upstream Rho1 GTP exchange factors Rom2 and Tus1. Overall, the synthetic genetic network around PKC1 directly and efficiently identifies known and novel components of PKC signaling in yeast.

* Corresponding author. Mailing address: Molecular Genetics and Integrative & Systems Biology, Faculty of Biomedical and Life Sciences, University of Glasgow, Anderson College Complex, 54-56 Dumbarton Road, Glasgow G11 6NU, United Kingdom. Phone: (141) 330-6135. Fax: (141) 330-4878. E-mail: J.Gray{at}bio.gla.ac.uk

{triangledown} Published ahead of print on 19 September 2008.

{dagger} Present address: Molecular Oncology and Breast Cancer Program, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.

Eukaryotic Cell, November 2008, p. 1880-1887, Vol. 7, No. 11
1535-9778/08/$08.00+0     doi:10.1128/EC.00222-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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