UT SOUTHWESTERN MEDICAL CENTER
DEPARTMENT of PHARMACOLOGY
PROTEOLYTIC MECHANISMS in CELL SIGNALING
Life and death decisions are of paramount importance to all cells. Paradoxically, emerging evidence depicts a new regulatory landscape in metazoans where the same proteolytic machinery supports both outcomes of life and death. This duality suggests an unprecedented network of factors differentially regulating these activities for which we have no understanding. Our lab is working to unmask these ancient pathways.
The over-arching theme of the Weaver Lab is to deeply interrogate how proteolytic mechanisms mediate seemingly contradictory physiological functions. Current lines of inquiry include: (1) how caspases and other proteolytic factors distinguish distinct substrates, (2) how proteolytic factors sculpt gene expression dynamics and (3) what upstream inputs license one proteolytic activity over another. Our long-term objective is to illuminate the conserved programs regulating these fundamental cellular processes.
Deciphering these novel regulatory paradigms is essential to understanding a broad spectrum of disease processes. Pathological outcomes reflect critical tradeoffs of cell turnover, cell fate, or tuning of stress responsiveness such as in the contexts of cancers, degenerative diseases, and immune disorders. These maladies underscore the importance of cells to sense their internal and external environments and respond accordingly. How cells and tissues integrate diverse inputs during development and aging remain wide open areas of research. Our goal is to resolve these long-standing mysteries.
To tackle these challenging questions, we employ a multi-disciplinary approach combining genetics, proteomics, transcriptomics, metabolomics, advanced imaging and biophysical analyses. The Weaver lab utilizes C. elegans, mammalian cell culture, and in vitro models. Equipped with powerful tools, we are setting out to understand how proteolytic mechanisms regulate basic biological processes and how these activities are integrated across tissues within animals.
DR. BENJAMIN WEAVER
Assistant Professor &
Virginia Murchison Linthicum Scholar in Medical Research
DR. YI MIAO WEAVER
Sr. Research Scientist
Structure function studies of proteolytic factors
DR. WANG YUAN
Caspases and p38 MAPKs in development and aging
DR. HAI WEI
Caspases in stress responses
FRANCISCO CALVA MORENO
MSTP Graduate Student
Center for Regenerative Science and Medicine Fellowship
UBR E3 ligases in development and disease
Graduate School of Biomedical Sciences
Cell signaling mechanisms in development and stress
STARS Summer Student
Variant calling of suppressor mutations regulating stemness
WE ARE STILL
Graduate student applicants: Apply through the umbrella
Ph.D. Program and send Ben an email of interest.
Post-Doc and Technician Applicants: send Ben your letter of interest.
Current Priorities and Training Environment
The Weaver lab is multidisciplinary and employs state of the art methods in CRISPR mutagenesis, genetics, biochemistry, proteomics, transcriptomics, metabolomics, and advanced imaging to analyze dynamic cellular processes and how they are integrated across distinct cell types within animals. Using C. elegans, mammalian cell culture, and in vitro models, our unified goal is to understand how proteolytic factors regulate critical cell signaling decisions. Trainees will learn cutting-edge methodologies in diverse disciplines. We are actively working on several exciting fronts. Now is an exceptional time to use advanced technologies to examine fundamental biological problems.
As an emerging regulatory paradigm, our unpublished findings suggest an array of genes work with caspases to support the viability of cells. Using proteomic, genetic, and cell biology approaches, we are probing how proteolytic factors integrate diverse inputs to mediate cellular outputs. Several grand challenges to solve include: (1) Will these pathways act discretely to regulate independent sets of genes or act broadly coordinating many processes? (2) What developmental and environmental signals activate or inhibit these proteolytic functions? (3) How are these proteolytic functions compartmentalized within a cell to prevent activating cell death? and (4) How does alteration of these pathways contribute to diverse disease processes? Solving these fundamental cellular processes will be broadly illuminating.
STRESS & AGING
Throughout metazoans, p38 MAPKs are critical to initiate stress responses. We recently showed that CED-3 caspase antagonizes a p38 MAPK-dependent pathogen response to promote development.
We are using advanced CRISPR methods combined with omics-based approaches and advanced imaging to understand how this pathway is dynamically regulated throughout animal lifespan. What tissues are important for p38 MAPK regulation within an animal? Beyond innate immunity, does p38 MAPK regulate other targets?
We previously demonstrated that a non-canonical caspase function is necessary for temporal cell fate patterning to limit symmetric cell divisions at a critical developmental window. We are expanding these studies to understand the roles of other proteolytic factors in cell fate decisions.
Across nematodes, flies, and mammals, caspases have been found with critical non-canonical functions blocking stemness and supporting differentiation. We are using genetic and biochemical methods to understand how a given caspase with both cell death and stemness-blocking functions is distinctly regulated.
We recently showed that CED-3 caspase requires a UBR-type E3 ubiquitin ligase to efficiently cleave and degrade LIN-28 in vivo. We further showed that the caspase and E3 ligase physically interact. We are using biochemical and biophysical methods to understand how proteolytic factors recognize distinct substrates.
Proteolytic Activation of Fatty Acid Synthase Signals Pan-Stress Resolution
Wei H, Weaver YM, Yang C, Zhang Y, Hu G, Karner CM, DeBerardinis RJ, Weaver BP
Modulating p38 MAPK Signaling by Proteostasis Mechanisms Supports Tissue Integrity during Growth and Aging
Yuan W, Weaver YM, Earnest S, Taylor CA, Cobb MH, Weaver BP
Balancing p38 MAPK Signaling with Proteostasis Mechanisms Supports Tissue Integrity during Aging in C. elegans
Yuan W, Weaver YM, Earnest S, Taylor CA, Cobb MH, Weaver BP bioRxiv July 12, 2022
Now published in Nature Communications
Non-Canonical Caspase Activity Antagonizes p38 MAPK Stress-Priming Function to Support Development
Weaver BP*, Weaver YM, Omi S, Yuan W, Ewbank JE, Han M
Featured in Development or Disease: Caspases Balance Growth and Immunity in C. elegans
Olya Yarychkivska and Shai Shaham Developmental Cell 53(3): 259-260
Tag team: Roles of miRNAs and Proteolytic Regulators in Ensuring Robust Gene Expression Dynamics.
Weaver BP*, Han M
Coupled Caspase and N-End Rule Ligase Activities Allow Recognition and Degradation of Pluripotency Factor LIN-28 during Non-Apoptotic Development.
Weaver BP*, Weaver YM, Mitani S, Han M
Featured in Partners in Crime
Barbara Conradt Developmental Cell 41(6): 573-574
Time to move the fat.
Weaver BP*, Sewell AK, Han M
CED-3 caspase acts with miRNAs to regulate non-apoptotic gene expression dynamics for robust development in C. elegans.
Weaver BP, Zabinsky R, Weaver YM, Lee ES, Xue D, Han M
Featured in Development: Cell Death Machinery Makes Life More Robust
Cristina Aguirre-Chen and Christopher M Hammell eLife 3:e05816
Also featured in For Caspases, An Escape from Death
Beverly A Purnell Science 347(6218): 142-143
Joining us as a rotation student, let's hope Tatiana finds C. elegans as fun as the rest of us do!!
Wang's first paper is now published at Nature Communications! More to come very soon!!
Welcome Prerith Arunkumar!
Joining us as a rising Senior, Prerith has chosen to embark on his science journey with us as a STARS student this summer.
Ben gave a talk on the lab's exciting recent findings of FASN in stress responses at the Mechanisms of Metabolic Signaling meeting at Cold Spring Harbor.
Ben is honored to join the 2023 TAMEST meeting as the protege of Dr. David Mangelsdorf Professor and Chair of Pharmacology.
Yi was honored to receive the Gilman Special Opportunities in Pharmacology Award.
Welcome George Jose!
Joining us as an undergraduate from UT Dallas, George has received a presitigious Green Fellowship and has chosen to spend the spring semester with us for undergraduate research.
Ben was thrilled to deliver the Alvin Sarachek Research Seminar at his alma mater in the Department of Biological Sciences of Wichita State University.
Ben gave a talk about the lab's exciting recent findings on caspase regulation of p38 MAPK signaling controlling neuroprotection during aging at the 2nd international Non-Lethal Roles of Cell Death Proteins meeting in Galway Ireland.
Francisco was awarded a prestigious graduate fellowship from the Hamon Center for Regenerative Science and Medicine!
Ben gave a talk about the lab's exciting recent findings on caspase regulation of p38 MAPK signaling controlling neuroprotection during aging at the Metabolism, Aging, Pathogenesis, and Stress in C. elegans meeting in Madison Wisconsin.
Wang's first author paper posted on bioRxiv
Ben was honored to join the 2022 TAMEST meeting as the protege of Dr. Melanie Cobb, Professor of Pharmacology.
Awesome Jobs Hai and Wang!
Hai gave a terrific talk and Wang gave an exceptional poster at the Physiology retreat!
Awesome Job Francisco!
Francisco gave a terrific talk at the CMB graduate symposium!
Move is Done!
Everyone pitched in and we finally moved into our newly-renovated space. Awesome microscopy and tissue culture facilities.
Francisco passed his qualifying exams!
Wang wins the Spring Pretty Gel Competition!
Our newest paper out in Dev Cell! Good start!
Welcome Dr. Hai Wei!
After graduate school in Munich, Hai joins the lab for post-doctoral studies.
Welcome Francisco Calva Moreno!
Following undergraduate studies in Philly, Francisco joins the lab for graduate studies.
Ben gave a talk about the lab's recent exciting findings on caspase-mediated regulation of pathogen response during development at the 1st international Non-Apoptotic Roles of Cell Death Proteins meeting in Rehovot Israel.
Congratulations Weaver Lab!
Ben's MIRA grant funded through NIGMS!
Welcome Dr. Wang Yuan!
After training in Iowa, Wang joins the lab for post-doctoral studies.
Congratulations Weaver Lab!
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.
Thank You Min and All of the Han Lab!
Ben and Yi worked in Min Han's HHMI lab at CU Boulder where we discovered a non-canonical function for CED-3 caspase and UBR-1 E3 ligase in cell fate determination.
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 from around the globe. Here are a few glimpses of having 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 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, and starchy noodles! Wang's philosophy: best part is that you can add anything, this dish knows no limits!
NON-CANONICAL BARBECUE by BEN
Savory homemade marinades with thyme, cumin and bay leaf combined with hickory and cherry smoke for a decadent 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.
LAB BOWLING PARTY
Celebrating Francisco passing qualifying exam!!
AGING MEETING 2022
Great colleagues, great science, great weather in Madison...You just can't beat it!
LAB GOLF PARTY 2023
Celebrating Hai's paper!!
Interested in joining? We would love to hear from you.
benjamin.weaver [at] utsouthwestern.edu
This website reflects only the views of the author and is not a publication of UT Southwestern, which bears no responsibility for its content.
UT Southwestern Medical Center
6001 Forest Park Rd
Dallas, TX 75390 USA