Our laboratory studies the molecular machinery used by cells to interpret extracellular signals and transduce them to the nucleus to effect changes in gene expression. This process is of fundamental biological importance. The accurate response to extracellular signals results in a cell's decision to proliferate, differentiate, or die, and it is critical for normal development and physiology. The disregulation of this machinery underlies the unwarranted expansion or destruction of cell numbers that occurs in human diseases like cancer, autoimmunity, hyperinflammatory states, and neurodegenerative disease.

Currently, we study signaling pathways that are important in innate immunity, adaptive immunity, and in cancer, paying particular attention to pathways that regulate the activity of the pleiotropic transcription factor NF-κB. We are interested in these broad questions:

• What are the biochemical mechanisms of signal transduction?
• How is the input-output specificity determined so that each particular ligand or extracellular cue induces the appropriate cellular response?
• How does the molecular specificity at the atomic level underlie biological specificity at the organismal level?
• How are signaling pathways disregulated in human disease and can we use this knowledge to develop new therapeutics?
• Can we use our understanding of signaling mechanisms to design novel, artificial signaling circuits for research and therapeutic purposes, for example, to control cell fate?

The activation of NF-κB by antigen receptor engagement is a critical requirement for the activation of lymphocytes in the adaptive immune response. Using a novel expression cloning strategy designed to isolate molecules that signal to NF-κB in lymphocytes, we cloned CARD11, a multiprotein adaptor molecule and member of the MAGUK family of signaling proteins. We demonstrated that CARD11 plays a pathway-specific, factor-specific role in the activation of NF-κB downstream of T cell receptor signaling (Pomerantz, Denny, and Baltimore, 2002). We are currently investigating the biochemical mechanisms by which CARD11 transduces signals from the T cell receptor to NF-κB.

We have used our expression cloning strategy (Pomerantz, Denny, and Baltimore, 2002) to clone several novel signaling molecules that signal the activation of the NF-κB or NFAT transcription factors. We will study their biological roles and characterize their mechanisms of action. We are also investigating whether our protocol is adaptable for the isolation of signaling molecules that regulate other transcription factors that influence the decision to proliferate, differentiate, or die, and that are disregulated in human disease.

We are interested in testing our understanding of signal transduction by applying mechanistic insights toward the design of novel artificial cellular circuits. Our goal is to develop heterologous circuitry that would provide new tools for controlling gene expression to be used in biological research and to engineer cell fate decisions in novel therapeutic approaches.

Sommer K, Guo B, Pomerantz JL, Bandaranayake AD, Moreno-Garcia ME, Ovechkina YL, Rawlings DJ. (2005) Phosphorylation of the CARMA1 linker controls NF-kappaB activation. Immunity 162: 4030-4036 [PubMed]

Pomerantz JL, Denny EM, and Baltimore D. (2002) CARD11 mediates factor-specific activation of NF-kappaB by the T cell receptor complex. EMBO.J. 286(2): 196-207 [PubMed]

Pomerantz JL, and Baltimore D. (2002) Two pathways to NF-kappaB. Mol. Cell 201(11):1741-52 [PubMed]

Wurtz NR, Pomerantz JL, Baltimore D, and Dervan PB. (2002) Inhibition of DNA binding by NF-kappaB with pyrrole-imidazole polyamides. Biochemistry 201(11):1753-9 [PubMed]

Pomerantz JL, and Baltimore D. (2000) Signal transduction – A cellular rescue team. Nature 42(1):104-112 [PubMed]

Pomerantz JL, and Baltimore D. (1999) NF-kappaB activation by a signaling complex containing TRAF2, TANK, and TBK1, a novel IKK-related kinase. EMBO.J. 179, 1317-1330 [PubMed]

Pomerantz JL, Wolfe SA, and Pabo CO. (1998) Structure-based design of a dimeric zinc finger protein. Biochemistry 8, 451-460 [PubMed]

Pomerantz JL, Pabo CO, and Sharp PA. (1995) Analysis of homeodomain function by structure-based design of a transcription factor. Proc. Natl. Acad. Sci. USA 190, 815-825 [PubMed]

Pomerantz JL, Sharp PA, and Pabo CO. (1995) Structure-based design of transcription factors. Science 7:664-665 [PubMed]

Kristie TM, 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 Chemistr 14:751-761 [PubMed]

Pomerantz JL, and Sharp PA. (1994) Homeodomain determinants of major groove recognition. Biochemistry 172: 5346-5355 [PubMed]

Pomerantz JL, Kristie TM, and Sharp PA. (1992) Recognition of the surface of a homeo domain protein. Genes & Development 194: 719-732 [PubMed]

Pomerantz JL, Mauxion F, Yoshida M, Greene WC, and Sen R. (1989) A second sequence element located 3' to the NF-kappaB binding site regulates IL-2 receptor-alpha gene induction. J. Immunol. 192:1697-1706 [PubMed]

Rothenberg ME, 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 162: 6401-6409 [PubMed]