Our Science – Weissman Website

Allan M. Weissman, M.D.

Laboratory of Protein Dynamics and Signaling Laboratory Chief Laboratory of Protein Dynamics and Signaling National Cancer Institute at Frederick 1050 Boyles Street, Building 560, Rm 22-103 Frederick, MD 21702-1201 Phone:   301-846-1222 Fax:   301-846-1666 E-Mail:   amw@nih.gov

Biography

Dr. Allan Weissman received his B.S. from Stony Brook University and his M.D. from Albert Einstein College of Medicine in 1981. After a residency in Internal Medicine at Washington University, he came to NIH where he was a post-doctoral fellow in NICHD. In 1989, he joined the NCI as an independent investigator. In 2001 he was appointed Laboratory Chief and is currently the Chief of the Laboratory of Protein Dynamics and Signaling.

Research

The components of the ubiquitin system comprise a highly complex and finely tuned set of mechanisms whereby the fate and function of specific proteins are regulated. Modification of proteins with ubiquitin impacts on almost all cellular processes by targeting proteins for degradation in the 26S proteasome, affecting the trafficking of proteins within the cell in numerous ways, in activating signal transduction pathways, modulating gene expression and in DNA repair. Ubiquitylation is a hierarchical pathway with one (maybe two) ubiquitin-activating enzymes (E1), over 30 different ubiquitin conjugating enzymes (E2s) and perhaps as many as a 1000 different potential ubiquitin ligases (E3s). Ubiquitin ligases interact with E2s that have been loaded with ubiquitin, recognize specific substrates and mediate the transfer of ubiquitin to substrates where stable isopeptide linkages are formed and in many cases chain of ubiquitin are generated.

While we are interested in all aspects of the ubiquitin system, work in our laboratory is primarily focused on ubiquitin protein ligases, their interactions with specific E2s, structure-function relationship and the roles of these protein in modulating critical cellular processes, particularly those that are associated with cancer and other human diseases. We also have an interest in the discovery of inhibitors of specific components of the ubiquitin system that may serve as the basis for novel therapeutics.


Structure-Function Relations and Substrate Identification for Ubiquitin Ligases

There are a limited number of ubiquitin ligase domains, however, within these families there are a variety of other regions that appear to play roles in modulating the activity of ligases. Ongoing studies in the laboratory are oriented towards determining the role that various domains and structural features play in the function of ubiquitin ligases and identifying specific substrates for these ligases. Ubiquitin ligases currently under study include AO7 - which has been implicated in signaling through NF-KB, Parkin - a ubiquitin ligase frequently mutated in familiar Parkinson's Disease and ubiquitin ligases implicated in degradation from the ER (see below).


Determining the fate of transmembrane proteins in the secretory pathway

A major area of interest in our laboratory is in understanding the mechanisms responsible for targeting proteins for endoplasmic reticulum-associated degradation (ERAD). This represents a major mechanism whereby misfolded and unassembled proteins are targeted for degradation and also plays important roles in responses to ER-stress and in regulating critical regulatory proteins. We have characterized a specific ubiquitin-conjugating enzyme, known as Ube2g2 or MmUbc7 that is critical to this process. We more recently have determined that a polytopic membrane protein originally characterized as the tumor Autocrine Motility Factor Receptor isoform 2 (AMFR) also known as gp78 or RNF45 is a ubiquitin ligase intrinsic to the ER that functions together with Ube2g2 to mediate protein degradation.

Our research has uncovered a complex domain structure for gp78, which includes a RING finger, a Cue domain that binds ubiquitin and a novel and highly specific binding site for Ube2g2. These domains function coordinately to mediate the ubiquitylation of substrates both in vitro and in cells. Further structure-function analyses of these domains and other regions of gp78 is currently underway in the lab as well as studies oriented towards understanding substrate specificity and mechanisms by which other ubiquitin ligases implicated in ERAD function either alone or together with gp78.

AMFR was first characterized as a factor the expression of which was associated with the aggressiveness of cancers. Given this history and the increasing evidence for roles for issues related to ER stress and the unfolded protein response in cell survival, we are evaluating that gp78 might play in tumor growth and in metastasis in animals and whether there are specific proteins targeted by gp78 that might be responsible for its postulated role in human malignancy.


Inhibitors of the ubiquitin conjugating system

The discovery that the RING finger represents a ubiquitin ligase domain has led us to become involved in the search for inhibitors of specific ubiquitin ligases whose activity may play an important role in cancer. This work, in collaboration with Dr. Karen Vousden and IGEN/MSD has led to the discovery of a family of inhibitors of Hdm2, an E3 that plays a critical role in regulating levels of p53, a critical tumor suppressor and the 'guardian of the genome'. Current work in this area is directly towards developing more potent inhibitors based on the molecules we have characterized as well as working with NCI Molecular Targets Development Program towards the identification and characterization of Hdm2 inhibitors from natural product extracts. A side benefit of our screening efforts has been the discovery of a family of small molecules that exhibit relative specificity towards inhibiting E1 and which specifically kill transformed cells.

This page was last updated on 6/12/2008.