Research
Functional Specificity and Design of Signal Transduction
Pathways
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-kB. 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?
Examples of current projects:
The biochemistry of antigen receptor signaling in B and T lymphocytes
The activation of NF-kB 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-kB 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-kB 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-kB.
Expression cloning of signaling molecules that regulate NF-kB, NFAT, and other
transcription factors
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-kB 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.
Design of novel signal transduction pathways for cell engineering
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.
Publications
Rothenberg, M.E., J.L. Pomerantz, W.F.
Owen, Jr., S. Avraham, R.J. Soberman, K.F. Austen,
and R.L. Stevens. (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.
PubMed
Reference
Pomerantz, J.L., F. Mauxion, M. Yoshida, W.C. Greene, and R. Sen. (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.
PubMed
Reference
Pomerantz, J.L., T.M. Kristie, and P.A. Sharp. (1992) Recognition of the surface
of a homeo domain protein. Genes & Development 6, 2047-2057.
PubMed
Reference
Pomerantz, J.L., and P.A. Sharp. (1994) Homeodomain determinants of major groove
recognition. Biochemistry, 33, 10851-10858.
PubMed
Reference
Kristie, T.M., J.L. Pomerantz, T.C. Twomey, S.A. Parent, And P.A. Sharp. (1995)
The cellular C1 factor of the herpes simplex virus enhancer complex is a family
of polypeptides. Journal of Biological Chemistry, 270, 4387-4394.
PubMed
Reference
Pomerantz, J.L., P.A. Sharp, and C.O. Pabo. (1995) Structure-based design of
transcription factors. Science, 267, 93-96.
PubMed
Reference
Pomerantz, J.L., C.O. Pabo, and P.A. Sharp. (1995) Analysis of homeodomain function
by structure-based design of a transcription factor. Proc. Natl. Acad. Sci.USA,
92, 9752-9756.
PubMed
Reference
Pomerantz, J.L., S.A. Wolfe, and C.O. Pabo. (1998) Structure-based design of
a dimeric zinc finger protein. Biochemistry, 37, 965-970.
PubMed
Reference
Pomerantz, J.L. and D. Baltimore. (1999) NF-kB activation by a signaling complex
containing TRAF2, TANK, and TBK1, a novel IKK-related kinase. EMBO J., 18, 6694-6704.
PubMed
Reference
Pomerantz, J.L. and D. Baltimore. (2000) Signal transduction – A cellular
rescue team. Nature, 406, 26-29.
PubMed
Reference
Wurtz, N.R., J.L. Pomerantz, D. Baltimore, and P.B. Dervan. (2002) Inhibition
of DNA binding by NF-kB with pyrrole-imidazole polyamides. Biochemistry, 41,
7604-7609.
PubMed
Reference
Pomerantz, J.L., and D. Baltimore. (2002) Two pathways to NF-kB. Mol. Cell, 10,
693-695.
PubMed
Reference
Pomerantz, J.L., E.M. Denny, and D. Baltimore. (2002) CARD11 mediates factor-specific
activation of NF-kB by the T cell receptor complex. EMBO J., 21, 5184-5194.
PubMed
Reference
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