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. We aim to illuminate the conserved programs regulating 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 or stress responsiveness such as in the contexts of cancers, degenerative diseases, and immune disorders. These pathologies 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
Physical interactors of UBR E3 ligases in development
2022 Lab Celebration
WE ARE STILL RECRUITING!!
Grad Student applicants: Apply through the umbrella program and send Ben an email.
Post-Doc and Technician applicants: email Ben with your letter of interest.
Current Priorities and Training Environment
The Weaver lab is interdisciplinary and employs state of the art CRISPR mutagenesis, genetic, biochemical, proteomic, transcriptomic, metabolomic, and imaging methods to analyze dynamic processes in 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 cell signaling decisions. Understanding these mechanisms is crucial to diverse disease etiologies including cancers, degenerative diseases, and developmental disorders. Our lab has exceptional facilities for advanced microscopy, cell culture, and molecular biology. Trainees joining the Weaver lab will learn cutting-edge methodologies in diverse disciplines. We have an array of ongoing studies with several areas of emphasis indicated below. Trainees will have distinct projects developed with substantial mentoring.
We unmasked an array of genes working with caspase to support viability. Using proteomic, genetic, and cell biological approaches, we are probing how proteolytic factors integrate cell signaling.
GENE EXPRESSION DYNAMICS
We recently showed CED-3 caspase and PMK-1 p38 MAPK balancing stress-responsive and developmental functions. We are using a big data approach including genomics, proteomics, and translatomics to understand how broadly caspases and p38 MAPKs act in gene expression dynamics.
Using genetic, biochemical, and genomic approaches we demonstrated a non-canonical caspase function working in parallel to the miRISC pathway 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.
STRESS & AGING
Throughout metazoans, p38 MAPKs have stress response functions. We recently showed how CED-3 caspase blocks activation of a p38 MAPK-dependent pathogen response in development. We are using advanced CRISPR methods combined with omic approaches and advanced cell imaging to understand how developmental and stress-responsive states are dynamically regulated.
Across nematodes, flies, and mammals, classic cell death caspases have been found with critical non-canonical functions supporting cell vigor. We are using genetic and biochemical methods to understand how a given caspase with both cell death and cell vigor functions is differentially regulated.
We recently showed that the 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.
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
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 Dev Cell 53(3): 358-369
Featured in Development or Disease: Caspases Balance Growth and Immunity in C. elegans
Olya Yarychkivska and Shai Shaham Dev Cell 53(3): 259-260
Tag team: Roles of miRNAs and Proteolytic Regulators in Ensuring Robust Gene Expression Dynamics.
Weaver BP, Han M Trends Genet. 34(1):21-29
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 Dev. Cell 41(6):665-673
Featured in Partners in Crime
Barbara Conradt Dev Cell 41(6): 573-574
Time to move the fat.
Weaver BP, Sewell AK, Han M Genes Dev. 30(13):1481-1482
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 eLife e04265
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
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 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!
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 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.
Interested in joining? We would love to hear from you.
benjamin.weaver [at] utsouthwestern.edu
Just Started on Twitter: @WeaverScience
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