Paul J. Cullen

PhD

Paul J. Cullen.

Paul J. Cullen

PhD

Paul J. Cullen

PhD

Professor, Milton Plesur Excellence in Teaching Award
Director of Graduate Studies

Research Interests

Signal transduction and cell polarity

Contact Information

C532 Cooke Hall

Buffalo NY, 14260

Phone: (716) 645-4923

Fax: (716) 645-2975

pjcullen@buffalo.edu

Education

  • PhD, Washington University, Saint Louis

Office Hours

  • Friday: 2:00 - 5:00pm

Research Summary

Our lab is interested in signal transduction pathways. All cells sense and respond to changes in the environment. Sensing and relaying changes in the extracellular milieu is mediated by signal transduction pathways. One type of evolutionary conserved signaling pathway are Mitogen-Activated Protein Kinase (MAPK) pathways. MAPK pathways are found in all eukaryotes and function in diverse ways to regulate cell differentiation, cell cycle progression, and the response to stress. An interesting feature of MAPK pathways is that they can share components with other pathways in the cell. How pathways that function in integrated networks induce the ‘right’ response is not well understood. Furthermore, inappropriate regulation of MAPK pathways can lead to improper signaling, which is an underlying cause of diseases including cancers, immune diseases, inflammation, and neurodegenerative disorders.

Our laboratory uses the model organism budding yeast to study MAPK pathways. In yeast, MAPK pathways control the response to stress and orchestrate cell differentiation to specialized cell types. Using this model, we have been able to identify new regulators of MAPK pathways and new mechanisms for their regulation. For example, we showed that mucins that regulate MAPK pathways in yeast undergo processing and release of an inhibitory extracellular glycodomain. More recently, we have identified an adaptor that regulates and might help to insulate the pathway (the pathway we study shares components with other MAPK pathways). We are currently working on how positional cues impact MAPK pathway signaling through the Rho GTPase Cdc42. 

The specific MAPK that we study in our laboratory regulates a cell differentiation response called filamentous growth. Filamentous growth is a fungal-specific growth mode that occurs in yeast and many other fungal species. During filamentous growth, cells change their shape and grow as branched filaments. In some species of pathogenic microorganisms, filamentous growth is required for virulence. Among the signaling pathways that regulate filamentous growth is an ERK-type MAPK pathway called the filamentous growth (fMAPK) pathway. Studying how MAPK pathways regulate filamentous growth in yeast can shine light on MAPK-dependent differentiation responses in general as well as the molecular basis of fungal pathogenesis.

The proteins that regulate the fMAPK pathway in yeast have been identified by our laboratory and other laboratories. A signalling mucin-type glycoprotein (Msb2), together with polar landmarks, regulates the cell’s major polarity GTPase Cdc42p, which activates a canonical p21-MAPKKK-MAPKK-MAPK kinase cascade. Key questions surrounding the regulation of the fMAPK pathway remain unaddressed. One question is how does the mucin Msb2 regulate the GTPase module? A second question is how is a specific signal sent by a pathway that shares components with other MAPK pathways in the cell? Our lab is approaching these questions in different ways:

1. By the development and utilization of genomic and proteomic approaches, we have discovered and are continuing to identify proteins that regulate the filamentous growth pathway. For example, we used the fact that the extracellular domain of Msb2 is shed to develop a high throughput screening approach called secretion profiling to identify new regulators of Msb2/fMAPK.

2. By building new assays to measure and quantitate filamentous growth, we are learning more about the molecular basis of the response. We are currently utilizing genetics, microscopy, and bioinformatics analysis to define aspects of filamentous growth regulation.

3. Biochemistry, molecular biology, and in vivo protein-interaction approaches (e.g. two-hybrid analysis and FRET) are being employed, which are critical to determine how proteins that regulate MAPK pathways function to induce a response.

More recently, we have begun to focus on MAPK pathway regulation in fungal pathogens. Fungal infections are a worldwide health problem and are a leading cause of death in developing countries. They contribute to pneumonia, asthma, and blindness. Fungal infections also compound the morbidity of other diseases like tuberculosis. Candida albicans an opportunistic fungal species present as a normal flora in the majority of the human population. Under pre-disposing conditions in the host, this species can be pathogenic and cause infections. One of the major virulence factors involved in C. albicans pathogenesis is its conversion from the yeast to the hyphal form. Biofilm formation is another key virulence traits. Improved diagnosis and new anti-fungal drugs are recognized as key routes to improving patient survival. Among the major signalling pathways that regulate dimorphism in C. albicans is the Cek1 MAPK pathway, which is analogous to the fMAPK pathway in budding yeast. We are interested in understanding mucin-type Cek1 pathway signaling in C. albicans. In particular, we are interested in unique aspects of MAPK signaling regulation and responses in this organism.

Selected Publications

  • Colloidal Gels with Tunable Mechanomorphology Regulate Endothelial Morphogenesis (2019) Nair, S.K., Basu, S., Sen, B., Lin, M.S., Kumar, A.N., Yuan, Y., Cullen, P.J., Sarkar, D. Scientific Reports  9(1):1072.
  • Chow, J., Dionne, H.M, Prabhakar, A., Mehrotra, A., Somboonthum, J., Gonzalez, B., Edgerton, M., and Cullen, P.J. (2019) Aggregate Filamentous Growth Responses in Yeast mSPHERE V4(2) e00702-18.
  • Breitenbach, M., Rinnerthaler, M., Weber, M., Breitenbach-Koller, H., Karl, T. Cullen, P.J., Basu, S., Haskova, D., and Hasek, J. (2018) The defense and signaling role of NADPH oxidases in eukaryotic cells. Wien. Med. Wochenschr. 168: 286-299.
  • Sehgal, N.,  Sylves, M.E., Sahoo, A., Chow, J., Walker, S., Cullen, P.J., and Berry, J.O. (2018) CRISPR gene editing in yeast: An experimental protocol for an upper-division undergraduate laboratory course.Biochemistry and Molecular Biology Education doi: 10.1002/bmb.21175.
  • Chow, J., Notaro, M., Prabhakar, A., Free, S.J., and Cullen, P.J. (2018) Impact of Fungal MAPK Pathway Targets on the Cell Wall Journal of Fungi V4:93.
  • Norman, K.L, Shively, C.A., De La Rocha, A.J., Basu, S., Cullen, P.J., and Kumar, A. (2018) Inositol Polyphosphates Regulate and Predict Yeast Pseudohyphal Growth Phenotypes PLoS Genetics 14(6):e1007493.
  • González, B., Vázquez, J., Cullen, P.J, Mas, A., Beltran, G., and Torija, M.J. (2018) Aromatic amino acid-derived compounds induce morphological changes and modulate the cell growth of wine yeast species. Frontiers of Microbiology 9:670.
  • Kumar, R., Breindel, C., Saraswat, D., Cullen, P.J., and M. Edgerton (2017) Candida albicans Sap6 amyloid regions function in cellular aggregation and zinc binding, and contribute to zinc acquisition. Scientific Reports 7:1p2908.
  • Gonzalez, B. Mas, A., Beltran, G., Cullen, P.J., Torija, M.J. (2017) Retrograde Mitochondria Pathway Regulates Ethanol-Inducible Filamentous Growth in Yeast Frontiers in Physiology 8:148. doi: 10.3389/fphys.2017.00148.
  • Woolford, C.A., Lagree, K., Xu, W., Aleynikova, T., Adhikari, H., Sanchez, H., Cullen, P.J., Lanni, F., Andes, D.R., and AP Mitchell (2016) Biofilm formation in the absence of Candida albicans biofilm transcriptional activators. PLoS Genetics. DOI:10.1371/journal.pgen.1006487.
  • Basu, S., Vadaie, N., Pradhakbar, A. Li, B., Pitoniak, A., Adhikari, H., Chavel, C., and Cullen, P.J. (2016) Spatial Landmarks Regulate a Cdc42p-Dependent MAPK Pathway to Control Differentiation and the Response to Positional Compromise. PNAS. 113(14):E2019-28.
  • Saraswat, D. Kumar, R., Pande, T. Edgerton M. and Cullen, P.J. (2016) Signaling Mucin Msb2 Regulates Adaptation to Thermal Stress in Candida albicans. Mol. Microbiology100(3):425-41.
  • Cullen, P.J. and Edgerton M. (2016) Unmasking Fungal Pathogens by Studying MAPK-Dependent Cell Wall Regulation in Candida albicans. Virulence. Apr 18:1-4.
  • Cullen, P.J. (2015) The Plate-Washing Assay: A Simple Test for Filamentous Growth in Budding Yeast. Cold Spring Harbor Laboratory Protocols. (2):168-71.
  • Cullen, P.J. (2015) Evaluating Yeast Filamentous Growth at the Single-Cell Level. Cold Spring Harbor Laboratory Protocols. (3): 272-5.
  • Cullen, P.J. (2015) Evaluating the Activity of the Filamentous Growth Mitogen Activated Protein Kinase Pathway in Yeast. Cold Spring Harbor Laboratory Protocols. (3):276-83.
  • Cullen, P.J. (2015) Biofilm/Mat Assays for Budding Yeast. Cold Spring Harbor Laboratory Protocols. (2): 172-5.
  • Cullen, P.J. (2015) Investigating Filamentous Growth and Biofilm/Mat Formation in Budding Yeast. Cold Spring Harbor Laboratory Protocols. (3): 235-8.
  • Adhikari, H., Caccamise, L.M., Pande, T., and Cullen, P.J (2015) Comparative Analysis of Transmembrane Regulators of the Filamentous Growth MAPK Pathway Uncovers Functional and Regulatory Differences.Eukaryotic Cell. 14(9):868-883.
  • Adhikari, H. Vadaie, N., Chow, J., Caccamise, L.M., Chavel, C.A., Li, B., Bowitch, A. Stefan, C.J., and Cullen, P.J. (2015) Role of the Unfolded Protein Response in Regulating the Mucin-Dependent Filamentous-Growth Mitogen Activated Protein Kinase Pathway. Molecular and Cellular Biology. 35(8):1414-32.
  • Adhikari, H. and Cullen, P.J. (2015) Role of Phosphatidylinositol Phosphate Signaling In the Regulation of the Filamentous Growth MAPK Pathway. Eukaryotic Cell. 14(4): 427-40.
  • Li, R. Puri, S. Tati, S. Cullen, P.J. and Edgerton, M. (2015) Candida albicans Cek1 MAPK signaling enhances fungicidal activity of salivary Histatin. Antimicrobial Agents and Chemotherapy. 59(6):3460-8.
  • Pitoniak A., Chavel C.A., Chow J., Smith J., Camara D., Karunanithi S., Li B., Wolfe K., Cullen P.J. (2015) Cdc42p-Interacting Protein Bem4p Regulates the Filamentous Growth MAP Kinase Pathway. Mol. Cell. Biol. Nov 10. pii: MCB.00850-14.
  • Chavel C.A., Caccamise L.M., Li B., Cullen P.J. (2014) Global regulation of a differentiation MAPK pathway in yeast. Genetics. V198(3):1309-28.
  • Adhikari, H. and Cullen P.J. (2014) Metabolic respiration induces AMPK- and Ire1p-dependent activation of the p38-Type HOG MAPK pathway. PLoS Genetics. V10(10):e1004734. doi: 10.1371/journal.pgen.1004734.
  • Puri, S., Kumar, R., Chadha, S., Tati S., Conti, H.R., Hube, B., Cullen, P.J, Edgerton M. (2012) Secreted Aspartic Protease Cleavage of Candida albicans Msb2 Activates Cek1 MAPK Signaling Affecting Biofilm Formation and Oropharyngeal Candidiasis. PLoS ONE. 7(11):e46020.
  • Karunanithi S., and Cullen P.J. (2012) The Filamentous Growth MAPK Pathway Responds to Glucose Starvation Through the Mig1/2 Transcriptional Repressors in Saccharomyces cerevisiaeGenetics. 192(3):869-87.
  • Meem M.H. and Cullen P.J. (2012) The impact of protein glycosylation on Flo11-dependent adherence in Saccharomyces cerevisiaeFEMS Yeast Research. 12(7):809-18.
  • Karunanithi S, Joshi J, Chavel C, Birkaya B, Grell L, and P.J. Cullen (2012)Regulation of Mat Responses by a Differentiation MAPK Pathway in Saccharomyces cerevisiae. PLoS ONE. 7(4): e32294
  • Cullen, P.J. and G.F. Sprague (2012) The regulation of filamentous growth in yeast. Genetics. V190:23-49.
  • Cullen, P.J. (2011) Post-translational Regulation of Signaling Mucins. Current Opinion of Structural Biology. V21 p590-596.
  • Karunanithi, S., Vadaie, N., Chavel, C., Birkaya, B., Joshi, J., Grell, L, and P.J. Cullen (2010) Shedding of the Mucin-like Flocculin Flo11p Reveals a New Aspect of Fungal Adhesion Regulation. Current Biology. 20:1-7.
  • Chavel, C.A., Dionne, H.S., Birkaya, B. Joshi, J., and P.J. Cullen (2010) New Regulators of a Differentiation MAPK Pathway. PLoS Genetics. 19; 6(3):e1000883
  • Pitoniak, A., Birkaya, B., Dionne H.M., Vadaie, N., and P. J. Cullen (2009) The Signaling Mucins Msb2 and Hkr1 Differentially Regulate the Filamentation MAPK Pathway and Contribute to a Multimodal Response. Molecular Biology of the Cell. V20 p3101-3114.
  • Birkaya, B. Maddi, A., Joshi, J., Free, S.J., and P.J. Cullen (2009) The Role of the Cell Wall Integrity Pathway and Cdc42-Dependent MAPK Pathway in Cell Wall Remodeling During Filamentous Growth. Eukaryotic Cell. V8 p1118-1133.
  • Abdullah, U. and P.J. Cullen (2009) The tRNA Modification Complex Elongator Regulates the Cdc42-Dependent MAPK Pathway that Controls Filamentous Growth In Yeast. Eukaryotic Cell. V8 p1362-1372.
  • Vadaie, N., Dionne, H., Nickerson, S.R., Akajagbor, D.S., Krysan, D.J., and Cullen, P.J. (2008) Cleavage of the signaling mucin Msb2 by the aspartyl protease Yps1 is required for MAPK activation in yeast. J. Cell Biology. 181: 1073-1081.
  • Cullen, P.J. (2007) Signaling Mucins: The New Kids on the MAPK Block. Critical Reviews in Eukaryotic Gene Expression
  • P.J. Cullen, Xu-Friedman, R., Delrow, J., and G. F. Sprague, Jr. (2006).Genome-wide analysis of a protein glycosylation deficiency. FEMS Yeast Research.
  • Devit, M.J., Cullen, P.J. Branson, M., Sprague, G.F., and Fields, S. (2005).A novel genetic screening method based on artificially forced protein interactions. Genome Research. 15 (4):560-565.
  • Cullen, P.J., Sabbagh Jr., W., Graham, E., Irick, M. van Olden, E.K., Neal, C., Delrow, J., Bardwell, L., and George F. Sprague, Jr. (2004). A signaling mucin at the head of the Cdc42- and MAPK-filamentous growth pathway in yeast.Genes & Development. 18:1695-1708.
  • Smith, G.R., Given, S.A., Cullen, P.J., and Sprague, G.F. (2002)Identification and Characterization of GTPase Activating Proteins (GAPs) for Cdc42. Eukaryotic Cell. V1 p469-480. 
  • Cullen, P.J., and Sprague, G.F., Jr. (2002) The Glc7p-interacting protein Bud14p attenuates pheromone response, filamentous growth, and polarized growth in Saccharomyces cerevisiaeEukaryotic Cell. V1:884-894.
  • Cullen, P.J., and Sprague, G.F., Jr. (2002)The roles of bud-site-selection proteins in haploid invasive growth in yeast. Mol. Biol. Cell. 13:2990-3004.
  • Cullen, P.J. and Sprague, G.F. (2000) Glucose depletion causes haploid invasive growth in yeast. PNAS. 97: 13619-13624.*See Commentary on this article: Madhani, H.D. (2000) Interplay of intrinsic and extrinsic signals in yeast differentiation. PNAS. 97: 13461-13463.
  • Cullen, P.J., Schultz, J., Horecka, J., Stevenson, B., and Jigami, Y., and Sprague, G.F. (2000) Defects in protein glycosylation cause SHO1-dependent activation of a STE12 signaling pathway in yeast. Genetics. 155: 1005-1018.