Department of Physiology and
Tyrosine kinases play a central role in regulating cell
growth and differentiation. The mitogenic action of many
polypeptide growth factors is mediated by transmembrane
receptors with inducible tyrosine kinase activity.
Although transient activation of tyrosine kinases is a
necessary event in growth factor-induced mitogenesis,
constitutive activation of the enzymes may play a pivotal
role in the development and progression of cancer. For
example, Src is a tyrosine kinase that is involved in
signal transduction events that control normal cell
growth, and is not oncogenic. Activated forms of Src,
however, have been linked to a variety of human cancers:
the activity of Src is increased in a large proportion of
primary human breast tumors as well as in approximately
80% of colon cancers. Similarly, some forms of human
chronic myelogenous leukemia (CML) and acute lymphocytic
leukemia (ALL) are characterized by a chromosomal
translocation that leads to deregulation of the Abl
Oncogenic tyrosine kinases are thought to induce
malignant growth by modulating the activity of
cytoplasmic and plasma membrane proteins. The major
research goals of our laboratory are: (1) to understand
how tyrosine kinases recognize their target proteins in
cells; (2) to determine how these enzymes are regulated
in normal cells; and (3) to develop strategies to block
the action of oncogenic tyrosine kinases. Work in the
laboratory is focused on nonreceptor tyrosine kinases
(Src, Hck, and Abl), as well as on the tyrosine kinase
domains of the human Neu, insulin, and IGF-I receptors.
For the IGF-I and insulin receptor kinases, a long-range
goal is to provide a molecular explanation for the
distinct biological activities of the two hormones by
comparing the specificities of their respective
In addition to their tyrosine kinase
catalytic domains (green), Src family kinases possess
amino-terminal regulatory regions termed SH3 domains
(blue) and SH2 domains (orange). These modular domains
mediate intramolecular and intermolecular interactions
that are important in signal transduction.
tyrosine kinases, both of these domains are
important in maintaining an inactive conformation
(see structure, right. Click the image for a
The structure of
the Src-family tyrosine kinase Hck, solved by Dr.
John Kuriyan and his
colleagues at Rockefeller University (Nature 385,
602-609). In collaboration with Dr. Kuriyan's
group, we showed that displacement of the SH3
domain causes a potent activation of the enzyme
(Nature 385, 650-653).
Two of the ongoing projects in the laboratory
investigate the roles of SH2 and SH3 domains in
signal transduction by Src-family kinases:
1. Activation of Src-family tyrosine
kinases. We recently showed that the SH3 domains
of Src family kinases have a major regulatory
role in controlling tyrosine kinase activity. For
example, binding of the HIV-1 protein Nef to the
SH3 domain of the Src-family kinase Hck activates
For more details, see: I.
Moarefi, M. LaFevre-Bernt, F. Sicheri, M. Huse,
C.-H. Lee, J. Kuriyan, and W.T. Miller (1997).
Activation of the Src-Family Tyrosine Kinase Hck
by SH3 Domain Displacement. Nature 385, 650-653.
2. SH2 and SH3 domains
assist tyrosine kinases in recognizing cellular
substrates. We are investigating processive
phosphorylation, a mechanism in which the SH2
domains bind to potential substrates and promote
phosphorylation by the catalytic domain:
For more details on this work, see: P. Pellicena,
K.R. Stowell, and W.T. Miller (1998). Enhanced
Phosphorylation of Src-family Kinase Substrates
Containing SH2 Domain Binding Sites. J. Biol.
Chem. 273, 15325-15328.