Paul Herman

Focus

Mechanisms controlling eukaryotic cell growth and proliferation.

Research interests

Keywords:

Growth control; Ras proteins; Cancer; cAMP-dependent protein kinase (PKA); Protein phosphorylation; Signal transduction; Stationary phase.

Research in my lab is focused on developing a better understanding of the mechanisms controlling cell growth and proliferation in eukaryotic cells. Our long term goals are to identify novel proteins important for proliferative control and to investigate whether these proteins might be useful targets for cancer therapy. For these studies, we have been using the yeast, Saccharomyces cerevisiae, as our model organism of choice. This yeast is ideally suited for this work as it can be readily manipulated by a vast collection of powerful molecular genetic techniques. In addition, previous work has shown that the mechanisms regulating cell proliferation have been highly conserved and many fundamental aspects of this control were first recognized in this budding yeast.

Our recent work has focused on the Ras protein signal transduction pathway and its role in the control of S. cerevisiae cell growth. The yeast Ras proteins have multiple effectors but the cAMP-dependent protein kinase, PKA, appears to be the most important for the Ras effects on cell growth. As a result, we have been extensively studying the Ras/PKA pathway and have recently identified targets of this pathway that are important for the control of RNA polymerase II transcription. Interestingly, this work has suggested a novel mode of transcriptional control whereby signaling pathways directly target components of the general RNA polymerase II transcription apparatus. This type of a control mechanism would allow the cell to effect large changes in gene expression with one regulatory step.

Another major effort in the lab is aimed at identifying the in vivo substrates of PKA that are relevant for the control of cell growth. Towards this end, we have been using both classical genetics and an evolutionary genomics approach that was developed in our lab. Both of these methods have successfully identified several novel PKA substrates that are presently being characterized in the lab. In addition, we have recently developed a novel assay that allows PKA substrates to be identified by their ability to bind to altered forms of this kinase. We are presently using this assay to screen for novel substrates of PKA and we are also testing whether this assay strategy will work for other protein kinases.

 

 

Publications

• Deminoff, S. J., S. C. Howard, A. Hester, S. Warner and P. K. Herman (2006) Using substrate-binding variants of the cAMP-dependent protein kinase to identify novel targets and kinase domains important for substrate interactions in Saccharomyces cerevisiae. Genetics 173: 1909-1917.
• Stephan, J. S. and P. K. Herman (2006) The regulation of autophagy in eukaryotic cells: Do all roads pass through Atg1? Autophagy 2: 146-148.
• Budovskaya, Y. V., J. S. Stephan, S. J. Deminoff and P. K. Herman (2005) An evolutionary proteomics approach identifies novel substrates of the cAMP-dependent protein kinase. Proceedings of the National Academy of Sciences 102: 13933-13938.
• Chang, Y.-W., S. C. Howard and P. K. Herman (2004) The Ras/PKA signaling pathway directly targets the Srb9 protein, a component of the general RNA polymerase II transcription apparatus. Molecular Cell 15: 107-116.
• Budovskaya, Y. V., J. S. Stephan, F. Reggiori, D. J. Klionsky and P. K. Herman (2004) The Ras/cAMP-dependent protein kinase signaling pathway regulates an early step of the autophagy process in Saccharomyces cerevisiae. Journal of Biological Chemistry 279: 20663-20671.