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Joel L. Pomerantz
Joel L. Pomerantz
Institute for Cell Engineering
733 N. Broadway
Baltimore MD 21205
Functional Specificity and Design of Signal Transduction Pathways
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.
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 CARD11. J Allergy Clin Immunol. 2018. 141 (5): 1818-1830. *authors contributed equally #co-senior authors
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. J. Biol Chem. 2016. 291(50): 25921-25936
Jattani RP, Tritapoe JM, Pomerantz JL. Cooperative Control of Caspase Recruitment Domain-Containing Protein 11 (CARD11) Signaling by an Unusual Array of Redundant Repressive Elements. J. Biol Chem. 2016. 291(16):8324-8336.
Jattani RP, Tritapoe JM, Pomerantz JL. Intramolecular Interactions and Regulation of Cofactor Binding by the Four Repressive Elements in the Caspase Recruitment Domain-Containing Protein 11 (CARD11) Inhibitory Domain. J. Biol Chem. 2016. 291(16):8338-8348.
Hamblet CE, Makowski SL, Tritapoe JM, Pomerantz JL. NK Cell Maturation and Cytotoxicity are Controlled by the Intramembrane Aspartyl Protease SPPL3. J. Immunol. 2016;196:2614-2626.
Pedersen SM, Chan W, Jattani RP, Mackie dS, Pomerantz JL. Negative Regulation of CARD11 Signaling and Lymphoma Cell Survival by the E3 Ubiquitin Ligase RNF181. Mol Cell Biol. 2016; 36:794-808.
Makowski, SL, Wang, Z, Pomerantz JL. A Protease-independent Function for SPPL3 in NFAT Activation. Mol Cell Biol. 2015. 35(2):451–467.
Chan, W., Schaeffer TB, Pomerantz JL. A quantitative signaling screen identifies CARD 11 mutations in the CARD and LATCH domains tht induce Bc110 ubiquitination and human lymphoma cell survival. Mol Cell Biol. 2013. 33(2): 429-443.
Lamason, R.L., Lew SM, and Pomerantz JL. 2010. Transcriptional target-based expression cloning of immunoregulatory molecules. Immunol. Res. 47:172-178.
Lamason, R.L., McCully RR, Lew SM, and Pomerantz JL. 2010. Oncogenic CARD11 mutations induce hyperactive signaling by disrupting autoinhibition by the PKC-responsive inhibitory domain. Biochemistry 49:8240-8250.
Lamason, R.L., Kupfer A, and Pomerantz JL. 2010. The dynamic distribution of CARD11 at the immunological synapse is regulated by the inhibitory kinesin GAKIN. Mol. Cell 40:798-809.
Yang, H.-C., Shen L, Siliciano RF, and Pomerantz JL. 2009. Isolation of a cellular factor that can reactivate latent HIV-1 without T cell activation. Proc. Natl. Acad. Sci.USA, 106: 6321-6326.
McCully, R.R. and Pomerantz JL. 2008. The Protein Kinase C-responsive inhibitory domain of CARD11 functions in NF-?B activation to regulate the association of multiple signaling cofactors that differentially depend on Bcl10 and MALT1 for association. Molecular and Cellular Biology 28:5668-5686.
Sommer, K., Guo B, Pomerantz JL, Bandaranayake AD, Moreno-Garcia ME, Ovechkina YL, and Rawlings DJ. 2005. Phosphorylation of the CARMA1 linker controls NF-kappaB activation. Immunity 23, 561-574.
Wurtz, N.R., Pomerantz JL, Baltimore D, and Dervan PB. (2002) Inhibition of DNA binding by NF-kB with pyrrole-imidazole polyamides. Biochemistry, 41, 7604-7609.
Pomerantz, J.L., and Baltimore D. (2002) Two pathways to NF-kB. Mol. Cell, 10, 693-695. PubMed Reference Pomerantz, J.L., Denny EM, and Baltimore D. (2002) CARD11 mediates factor-specific activation of NF-kB by the T cell receptor complex. EMBO J., 21, 5184-5194.
Pomerantz, J.L. and Baltimore D. (2000) Signal transduction пїЅ A cellular rescue team. Nature, 406, 26-29.
Pomerantz, J.L. and Baltimore D. (1999) NF-kB activation by a signaling complex containing TRAF2, TANK, and TBK1, a novel IKK-related kinase. EMBO J., 18, 6694-6704.
Pomerantz, J.L., Wolfe SA, and C.O. Pabo CO. (1998) Structure-based design of a dimeric zinc finger protein. Biochemistry, 37, 965-970.
Kristie, T.M., Pomerantz JL, Twomey TC, Parent SA, And Sharp PA. (1995) The cellular C1 factor of the herpes simplex virus enhancer complex is a family of polypeptides. Journal of Biological Chemistry, 270, 4387-4394.
Pomerantz, J.L., Sharp PA, and Pabo CO. (1995) Structure-based design of transcription factors. Science, 267, 93-96.
Pomerantz, J.L., Pabo CO, and Sharp PA. (1995) Analysis of homeodomain function by structure-based design of a transcription factor. Proc. Natl. Acad. Sci.USA, 92, 9752-9756.
Pomerantz, J.L., and Sharp PA. (1994) Homeodomain determinants of major groove recognition. Biochemistry, 33, 10851-10858.
Pomerantz, J.L., Kristie TM, and Sharp PA. (1992) Recognition of the surface of a homeo domain protein. Genes & Development 6, 2047-2057.
Pomerantz, J.L., Mauxion Yoshida FM, Greene WC, and Sen R. (1989) A second sequence element located 3' to the NF-kB binding site regulates IL-2 receptor-alpha gene induction. Journal of Immunology 143, 4275-4281.
Rothenberg, M.E., Pomerantz JL, Owen WF, Jr., Avraham S, Soberman RJ, Austen KF, and Stevens RL. (1988) Characterization of a human eosinophil proteoglycan, and augmentation of its biosynthesis and size by interleukin 3, interleukin 5, and granulocyte/macrophage colony stimulating factor. Journal of Biological Chemistry 263, 13901-13908.