Associate Professor
Nuclear magnetic resonance
Macromolecular structure and recognition
Finely tuned signal transduction cascades control all aspects
of cell renewal and cell death in normal, healthy cells. Altered gene
products introduce the possibility of imbalance within the tightly controlled
signaling networks that regulate cell growth and proliferation. This
is evident in the malignant form of the src tyrosine kinase, the viral
oncogene v-src. For this protein it has been shown (both biochemically
and structurally) that a single amino acid mutation disrupts the intramolecular
interactions responsible for inactivating the enzyme, thus rendering
the protein constitutively active(1). Aberrant signaling due to excess
phosphorylation ensues, leading to dire consequences for the cell and,
ultimately, for the organism. While the molecular details of the regulation
of some families of kinases (i.e. Src) have now been clarified, it is
not understood how the substrate binding and catalytic activity of other
families of protein tyrosine kinases are controlled. We are particularly
interested in a family of intracellular signaling molecules that is
exclusively expressed in hematopoeitic cells, and we have focused our
attention on the IL2-inducible tyrosine kinase (Itk), a member of the
Tec family of tyrosine kinases that is restricted to the T-cell lineage.
Structurally, Itk and related tyrosine kinases (Btk, Tec, Bmx and Rlk)
are quite distinct from the well-studied Src kinase family and are most
likely regulated by an alternative mechanism given the nature of the
differences in domain structure (2). The Andreotti laboratory makes
use of nuclear magnetic resonance (NMR) spectroscopy to determine the
three-dimensional structures of various domains of Itk and related family
members. Additionally, NMR is used to examine interactions between domains
to ultimately understand the regulatory apparatus of the Tec kinases
in molecular detail.
The overreaching goal of the research program is to gain a better understanding
of hematopoeitic cell signaling at the molecular level. Eventually,
the complex pathways that control signaling through cell surface receptors
such as the T cell receptor should be completely understood. Our knowledge
of such events will allow more complete under-standing of how malfunction
of the immune response can lead to autoimmune diseases and cancer.
(1) Cooper, J. A. and Howell, B. (1993) "The When
and How of Src Regulation", Cell, 73, 1051-1054.
(2) Mano, H. (1999) Tec family of protein-tyrosine kinases: an overview
of their structure and function. Cytokine & Growth Factor Reviews,
10, 267-280.
