Dissection of Galpha12-mediated Signaling Pathways through Mutational Analysis of Effector Interactions

Speaker:
Thomas E. Meigs, Ph.D.
GlaxoSmithKline Professor of Molecular & Chemical Biology, University of North Carolina at Asheville

Host:
Prof Patrick Casey
Senior Vice Dean, Duke‐NUS Graduate Medical School

Date:
Wednesday, 16 May 2012

Time:
4.00 PM — 5.00 PM

Venue:
Duke‐NUS Graduate Medical School
Amphitheatre, Level 2
 
Contact Person:
Dolliss Ang, Senior Vice Dean Office, Office of Research
Tel: 6516 7251 or Email: dolliss.ang@duke-nus.edu.sg

Synopsis:
Heterotrimeric G proteins transduce signals from a diverse set of cell surface receptors to the cell interior, leading to a variety of responses.  The alpha subunits of heterotrimeric G proteins are grouped into 4 subfamilies, including the G12 subfamily that consists of the closely related proteins Ga12 and Ga13.  These proteins have been implicated in signaling pathways that frequently become aberrant in cancer cells, including proliferation, migration, cytoskeletal rearrangements, apoptosis, and cell-cell adhesion.  However, efforts to study Ga12 signaling have been complicated by the discovery of nearly 20 putative effector proteins that interact with Ga12.  We have undertaken a comprehensive protein interaction study in which various target proteins of Ga12 are immobilized and assessed for binding to a series of cassette and single-residue mutants of constitutively active Ga12.  This approach has provided structural details of Ga12 interaction with several targets, including Rho-specific guanine nucleotide exchange factors, the C-terminus of polycystin-1, the scaffolding subunit of protein phosphatase-2A, and heat shock protein-90.  In addition, several of our mutants have provided molecular tools for investigating the role of specific Ga12:effector interactions in signaling pathways important in cancer progression, polycystic kidney disease, and potentially other physiological and pathological events.

Biography:
Prior to arriving at University of North Carolina at Asheville in 2003, Dr. Meigs held positions as a postdoctoral fellow at Duke University Medical Center from 1996-2000, and from 2000-2003 as a research scientist at Duke University’s Center for Chemical Biology. Dr. Meigs’ research addresses the broad question of how cells in the human body communicate with each other, and more specifically how these communication pathways are disrupted during cancer progression. The focus of his laboratory is to characterize and dissect the signaling pathways that involve a protein termed G12, which has been implicated by numerous studies in cancer progression, metastatic invasion, and embryonic development. His primary research goals are to identify the structural regions of G12 that govern its interaction with specific proteins that lie “downstream” of G12 in cellular communication pathways, and to reveal the roles of specific G12 : target protein interactions in particular aspects of G12-mediated changes in cells.