UT SOUTHWESTERN MEDICAL CENTER
DEPARTMENT of PHARMACOLOGY
Caspases and Proteolytic Mechanisms
Mediating Cell Fate, Signaling and Gene Expression Dynamics
Evidence across diverse phyla of metazoans depicts a new landscape for proteolytic factors, such as caspases, as not only effectors but key regulators of many cellular processes. In particular, genetic masking has hitherto limited our ability to observe many so-called "non-canonical" caspase functions that our work has recently brought to light. Now is an exciting time to be part of this rapidly emerging field.
The over-arching theme of the Weaver Lab is to deeply understand how proteolytic factors mediate diverse physiological functions. Along those lines, we have identified CED-3 caspase working to support a variety of cellular functions ranging from limiting symmetric divisions of a stem-like cell type during cell fate decisions to opposing p38 MAPK stress signaling and downstream gene expression program to promote development. We find that caspases often work with other regulatory pathways to achieve their non-canonical functions. Current lines of inquiry include: (1) how a given caspase is able to distinguish cell death from cell vigor substrates, (2) how proteolytic factors sculpt gene expression dynamics and (3) what upstream inputs license one proteolytic function over another.
To tackle these and other challenging questions, we employ a cross-disciplinary approach including genetics, proteomics and biophysical analyses. The Weaver lab utilizes C. elegans, mammalian cell culture, and biochemical models. Equipped with powerful tools, we are setting out to understand how proteolytic factors execute a potentially vast array of functions.
DR. BENJAMIN WEAVER
DR. YI MIAO WEAVER
Sr. Research Scientist
Structure function studies of proteolytic factors
DR. WANG YUAN
Roles of caspases and p38 MAPK in development
DR. HAI WEI
Caspases in stress responses
MSTP Graduate Student
UBR E3 ligases in development and disease
We are recruiting. If you're interested in joining an energetic and dynamic lab, contact us.
Current Priorities and Training Environment
The Weaver lab is interdisciplinary and employs state of the art genetic, biochemical, proteomic, transcriptomic, and biophysical approaches to analyze dynamic processes such as development, aging and stress responses. Using C elegans, mammalian cell culture, and in vitro models, our goal is to understand how proteolytic factors regulate critical cellular life or death decisions. Understanding the regulatory mechanisms of such decisions has broad impact on a variety of disease etiologies including cancers, degenerative diseases, and developmental disorders. Trainees joining the Weaver lab at UT Southwestern Medical Center will learn cutting-edge methodologies in diverse disciplines. Although highly interactive, members of the Weaver lab each have distinct projects developed with significant mentoring. This model allows each of us to focus on an exciting aspect of the larger whole. Our lab has a track-record of tackling fundamental biological processes from the level of phenotypes down to molecular mechanisms. We have an array of ongoing and future studies with several areas of emphasis indicated below.
GENE EXPRESSION DYNAMICS
We recently showed CED-3 caspase and PMK-1 p38 MAPK inversely regulate the expression of over 300 genes to balance stress-responsive and developmental functions. We want to know how broadly caspases and p38 MAPKs act in gene expression dynamics and how they alter the balance between protein degradation versus protein synthesis. We are using a big data approach including genomics, proteomics, and translatomics to address these questions.
Across nematodes, flies, and mammals, classic cell death caspases have been found with critical non-canonical functions supporting cell vigor. Thus, non-canonical functions of cell death caspases are not peculiar to any metazoan branch but rather the rule for caspases. We want to know how a given caspase with both cell death and cell vigor functions is differentially regulated. We are using genetic and biochemical methods to address this question.
We recently showed that the CED-3 caspase required a UBR-type E3 ubiquitin ligase to efficiently cleave and degrade LIN-28 in vivo. We further showed that the caspase and E3 ligase may form a complex. We want to know how proteolytic factors recognize distinct substrates to achieve diverse functions. We are using biochemical and biophysical methods to address this question.
Non-Canonical Caspase Activity Antagonizes p38 MAPK Stress-Priming Function to Support Development
Featured in Development or Disease: Caspases Balance Growth and Immunity in C. elegans
Tag team: Roles of miRNAs and Proteolytic Regulators in Ensuring Robust Gene Expression Dynamics.
Coupled Caspase and N-End Rule Ligase Activities Allow Recognition and Degradation of Pluripotency Factor LIN-28 during Non-Apoptotic Development.
Featured in Partners in Crime
Time to move the fat.
CED-3 caspase acts with miRNAs to regulate non-apoptotic gene expression dynamics for robust development in C. elegans.
Featured in Development: Cell Death Machinery Makes Life More Robust
Also featured in For Caspases, An Escape from Death
Still recruiting. Email letter of interest to Ben.
Dr. Hai Wei joins the lab for post-doctoral studies!
Francisco Calva-Moreno joins the lab for graduate studies!
Ben's MIRA grant funded through NIGMS!
Dr. Wang Yuan joins the lab for post-doctoral studies!
Ben's Welch Foundation grant funded!
Weaver Lab Established!
Ben and Yi get to work in the Department of Pharmacology at UT Southwestern Medical Center. Our central goals are to unravel how proteolytic factors impact diverse physiological outcomes and how these divergent functions are regulated.
While working in Min Han's HHMI lab at CU Boulder, we discovered that CED-3 caspase works in parallel to the miRISC pathway to limit supernumerary cell divisions of an epidermal stem-like cell type in C. elegans. We also found that this caspase required a UBR-type E3 ubiquitin ligase from the Arg/N-end rule to efficiently proteolytically cleave the non-apoptotic target LIN-28 in vivo.
Food for Thought
Not too surprisingly, biochemistry was born out of early efforts to perfect the enzymology and chemistry behind the fermentation of grains, fruits and milk to generate the varieties of dough, beer, wine and cheese that we know today. Here are a few glimpses of how we celebrate--as well as have some fun experimenting outside the lab.
TRADITIONAL PIE of CHINA by HAI
Power-packed gems filled with pork and cabbage. Seasoned with salt, soy sauce, oil, garlic, ginger, and green onion. Hai’s pro-tip: Make the outside bun with fermented dough. After lightly frying, pop these little party favorites into the oven for a crispy baked finish you won’t soon forget!
BEEF RAMEN NOODLES by YI
Fusion of ramen noodles seasoned lightly with onion and parsley for a hearty combo. Yi’s top-shelf ingredients…Tie this simple masterpiece together with Napa cabbage boiled in a soy-based broth. Add wood-smoked beef slices on top for a simple but super-delicious meal!
FAJITAS by FRANCISCO
Visually stunning arrangement of fajitas served with guacamole, beans, pico de galla and rice.
That’s not all! Francisco threw in a loaf of baked banana bread for a super-satisfying finish!
HOT POT by WANG
Traditional Chinese sensation that begins with a spicy soup stock and an assortment of meats, veggies, starchy noodles and you’re ready to roll! Wang's philosophy: best part is that you can add anything, this dish knows no limits! What more could you ask for?
NON-CANONICAL BARBECUE by BEN
Savory homemade marinades with thyme, cumin and bay leaf combined with hickory and cherry wood smoke for a decadent, savory flavor. How to plate? Ben likes to serve up his BBQ with grilled asparagus and homemade potato salad.
Hai joins the lab, New Years 2020!!!
Sorry Wang and Francisco...
We forgot to take pictures of your celebrations.
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Interested in joining? We would love to hear from you.
UT Southwestern Medical Center
6001 Forest Park Rd
Dallas, TX 75390
benjamin.weaver [at] utsouthwestern.edu