Research Overview
My laboratory is interested in the molecular mechanisms by which cells interpret signals from their environment that instruct them to proliferate, differentiate, or die by apoptosis. This process is of fundamental importance in the development and function of the immune system. The dysregulation of signal transduction underlies many diseases of the immune system including immunodeficiencies, autoimmunity, and cancers derived from immune cells. A particular focus of the lab is the regulation of NF-κB, a pleiotropic transcription factor that is required for normal innate and adaptive immunity and which is inappropriately activated in several types of human cancer. We have been studying how NF-κB is activated in B and T lymphocytes in response to antigen recognition by the T cell receptor (TCR) and B cell receptor (BCR) complexes. Recently we have characterized the molecular mechanisms by which a multi-domain adapter protein, CARD11, functions in TCR signaling to NF-κB. In response to antigen receptor engagement, CARD11 undergoes a transition from an inactive to an active protein scaffold, and recruits a cadre of signaling cofactors into a complex in a signal-responsive manner. Current research is aimed at understanding how the multiple domains of CARD11 function together to translate activating upstream signals from the antigen receptor into the coordinated signaling activity of associated cofactors. CARD11 has also been directly implicated in the dysregulated signaling to NF-κB that is a signature feature of a subtype of Diffuse Large B cell Lymphoma (DLBCL). This subtype of DLBCL requires constitutive NF-κB activation for oncogenic proliferation, and the knockdown of CARD11 in this lymphoma leads to apoptosis. Interestingly, several oncogenic mutations in CARD11 have been identified in human DLBCL. We are currently studying how the oncogenic CARD11 mutations result in hyperactive signaling to NF-κB. We are hopeful that a mechanistic understanding of these mutants might translate into the development of novel cancer therapeutics. In addition to the antigen receptor signaling pathway, we are also studying the regulation of NF-κB in other arms of the innate and adaptive immune system through the isolation and characterization of novel regulators of NF-κB activity. We have developed several novel expression-cloning approaches for identifying novel signaling molecules that either activate or inhibit NF-κB. Several novel signaling regulators are under current study. Other current projects include the study of novel regulators of the NFAT transcription factor, a key player in T cell activation and tolerance. It is our hope that the study of these signaling molecules will expand our understanding of how inflammatory and immune responses are controlled and they are dysregulated in human disease.
Cellular Stress and Cell Signaling | Genetics, Genomics and Gene Regulation | Immunology and Infectious Diseases
Lab Website
Pomerantz Lab – Lab Website
Selected Publications
- Bedsaul JR, Shah N, Hutcherson SM, Pomerantz JL. Mechanistic impact of oligomer poisoning by dominant-negative CARD11 variants. iScience, 2022.
- Hutcherson SM, Bedsaul JR, Pomerantz JL. Pathway-Specific Defects in T, B, and NK Cells and Age-Dependent Development of High IgE in Mice Heterozygous for a CADINS-Associated Dominant NegativeCARD11 Allele. Journal of Immunology, 2021.
- Wang Z, Hutcherson SM, Yang C, Jattani RP, Tritapoe JM, Yang YK, Pomerantz JL. Coordinated regulation of scaffold opening and enzymatic activity during CARD11 signaling. Journal of Biological Chemistry, 2019.
- Dadi H, Jones TA, Merico D, Sharfe N, Ovadia A, Schejter Y, Reid B, Sun M, Vong L, Atkinson A, Lavi S, Pomerantz JL, Roifman CM. Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11). Journal of Allergy and Clinical Immunology, 2018.
- Yang YK, Yang C, Chan W, Wang Z, Deibel KE, Pomerantz JL. Molecular Determinants of Scaffold-induced Linear Ubiquitinylation of B Cell Lymphoma/Leukemia 10 (Bcl10) during T Cell Receptor and Oncogenic Caspase Recruitment Domain-containing Protein 11 (CARD11) Signaling. Journal of Biological Chemistry, 2016.
