Patrick J. Brennwald, Ph.D.

Brennwald
pjbrennw@med.unc.edu
Lab Webpage

Lab Personnel

Brennwald Demonch 2 Brennwald Watson 2 Brennwald Watson2 2
Brennwald Rossi 2

Professor

  • B.A., Carleton College, 1985
  • Ph.D., University of Illinois, 1990
  • Postdoc, Yale University, 1990-94

Funding Sources

  • National Institutes of Health
  • The G. Harold and Leila Y. Mathers Foundation

Research Interests

Delivery of proteins to the proper place on the cell surface is important for a large number of cell biological processes, including the development of cellular asymmetry and polarity. The delivery of cell surface components is accomplished primarily by the delivery of transport vesicles that fuse with a specific region of the plasma membrane. We have been examining plasma membrane targeting events in the yeast, Saccharomyces cerevisiae, in order to take advantage of the genetic and cell biological tools available in this organism. SNARE proteins are thought to play a central role in the targeting and/or fusion of transport vesicles with the plasma membrane, and we have identified and extensively characterized a set of SNARE proteins which are required for cell surface transport in yeast. Our genetic and biochemical analysis of these proteins has led us to the identification of a new regulatory pathway involving the Rho GTPases Cdc42 and Rho3, as well as a novel Sec9 binding protein, related to the Drosophila tumor suppressor lethal giant larvae. Recent work from our lab suggests that Cdc42 function in exocytosis is restricted to very early in bud emergence while Rho3 appears to function in this regard throughout the cell cycle. This suggests that this pathway may be central to the overall coordination of the polarity of the actin cytoskeleton with the polarity of cell surface delivery. We are testing the model that the Rho-Cdc42/Sro7/Sec9 pathway is conserved in higher eukaryotic cells including polarized epithelial cells and neurons. These studies will have important implications in both understanding the function of Rho GTPases in exocytosis as well as in unraveling a novel mechanism for regulation of t-SNARE function at the plasma membrane. This regulation may represent a key mechanism by which eukaryotic cells regulate and coordinate the polarity of the actin cytoskeleton with the polarized delivery of protein and lipid to the cell surface. Finally studies from other systems suggest that loss of function in this pathway may be tied to the loss of polarity commonly observed during tumorigenesis.

Brennwald Image

Brennwald Image 2

Selected Publications

PubMed 1

  • Katz, L. and Brennwald, P. (2000). Testing the 3Q/1R "Rule": Mutational Analysis of the Ionic "Zero" Layer in the Yeast Exocytic SNARE Complex Reveals No Requirement for Arginine. Mol. Biol. Cell. 11, 3849-3858.
  • Brennwald, P. (2000) Reversal of Fortune: Do Rab GTPases Act on the Target Membrane? J. Cell Biol. J. Cell Biol. 149:1-4.
  • Adamo, J.E., Moskow, J.J., Gladfelter, A.S., Viterbo, D., Lew, D.J., and Brennwald, P.J. (2001). Yeast Cdc42 Functions at a Late Step in Exocytosis Specifically During Polarized Growth of the Emerging Bud. J. Cell Biol. 155, 581-592.
  • Müsch, A., Cohen, D., Yeaman, C.A., Nelson, W.J., Rodriguez-Boulan, E., and Brennwald, P.J. (2002) A Mammalian Homologue of the Drosophila Tumor Suppressor lethal (2) giant larvae Interacts with Basolateral Exocytic Machinery in MDCK cells. Mol. Biol. Cell. 13: 158-168.
  • Elbert, M., Rossi, G., and Brennwald, P. (2005). Yeast homologs of PAR-1, Kin1 and Kin2, show genetic and physical interactions with components of tthe exocytic machinery. Mol. Biol. Cell. 16(2):532-49.
  • Brennwald P. (2005). A new function for the Elongator complex: polarization of Rab activity? Dev Cell. 4: 454-456.
  • Gangar, A., Rossi, G., Andreeva, A., Hales, R., and Brennwald, P. (2004). Structurally Conserved Interaction of Lgl Family with SNAREs Is Critical to Their Cellular Function. Curr. Biol. 15: 1136-1142.
  • Roumanie, O., Wu, H., Molk, J.N., Rossi, G., Bloom, K., and Brennwald, P. (2005). Rho GTPase Regulation of Exocytosis in Yeast is Independent of GTP Hydrolysis and Polarization of the Exocyst Complex. J. Cell Biol. 170: 583-594.
  • Grosshans, B.L., Andreeva, A., Gangar, A., Niessen, S., Yates, J.R., Brennwald, P., Novick, P. (2006). The Yeast Lgl Family Member Sro7p is an Effector of the Secretory Rab GTPase Sec4. J. Cell Biol. 172: 55-66.
  • Wadskog, I., Forsmark, A., Rossi, G., Konopka, C., Oyen, M., Goksor, M., Ronne, H., Brennwald, P., and Adler, L. (2006). The yeast tumor suppressor homologue Sro7p is required for targeting of the sodium pumping ATPase to the cell surface. Mol. Biol. Cell. 12:4988-5003.
  • Hattendorf, D., Andreeva, A., Brennwald, P., and Weis, W. (2007). Structure of the yeast polarity protein Sro7 reveals a SNARE regulatory mechanism. Nature 446:567-71.
  • Brennwald, P., and Rossi, G. (2007). Spatial Regulation of Exocytosis and Cell Polarity: Yeast as a Model for Animal Cells. FEBS Letters. 581:2119-24.
  • Wu, H. Turner, C., Gardner, J., Temple, B., and Brennwald, P. (2010).  The Exo70 subunit of the Exocyst is an Effector for Both Cdc42 and Rho3 Function in Polarized Exocytosis. Mol. Biol. Cell. 21: 430-442.
  • Boulter, E.,  Garcia-Mata, R.,  Guilluy, C., Dubash, A., Rossi, G., Brennwald, P.J., and Burridge., K. (2010). Competitive Interactions with RhoGDI Regulate Rho Protein Homeostasis. Nature Cell Biology. 12: 477-483.
  • Wu, H. and Brennwald, P. (2010). The Function of Two Rho Family GTPases is Determined By Distinct Patterns of Cell Surface Localization.  Mol. Cell. Biol. 30:5207-5217.
  • Rossi, G. and Brennwald, P. (2011). Yeast Homologs of Lethal Giant Larvae and Type V Myosin Cooperate in the Regulation of Rab-Dependant Vesicle Clustering and Polarized Exocytosis. Mol. Biol. Cell. 6: 842-857.