invariant arginine as crucial for binding to activated 
growth factor receptors and other phosphotyrosine- 
containing proteins. This arginine may therefore be 
involved in the direct recognition of phosphotyro- 
sine. The elements w^ithin SH2 domains that confer 
their specificity for different phosphorylated sites 
are of the greatest interest. 
A Novel SH2-containing Protein Implicated 
in Mitogenic Signal Transduction 
The SH2-mediated association of signaling pro- 
teins such as PLC-7 and PI 3'-kinase with autophos- 
phorylated receptors appears important for their ac- 
tivation in response to growth factor stimulation. 
This suggests that SH2 domains are likely to be a 
hallmark of many tyrosine kinase targets and hence 
that the isolation of novel SH2-containing proteins 
may yield new information concerning the regula- 
tion of intracellular signal transduction in response 
to growth factors. 
In collaboration with Dr. Pier Giuseppe Pelicci, 
Dr. Jane McGlade has identified the SHC gene prod- 
ucts, which contain a single SH2 domain and a more 
amino-terminal glycine/proline-rich region. SHC 
overexpression induces growth factor-independent 
proliferation and malignant transformation of fibro- 
blasts. She proteins become highly tyrosine- 
phosphorylated following stimulation with a variety 
of growth factors and, through their SH2 domain, 
become physically associated with activated growth 
factor receptors. In addition, the 5//Cgene products 
appear to be prominent substrates of the v-Src, v- 
Fps, and Bcr-Abl oncoproteins. These results suggest 
that She proteins may be adaptors that couple a wide 
spectrum of receptor and nonreceptor tyrosine ki- 
nases to a signaling pathway that controls prolifera- 
tion. The tyrosine phosphorylation of She proteins 
induces their association with a 23-kDa polypep- 
tide, which is a good candidate for the downstream 
She target. 
It is evident that there are SH2-containing gene 
products, in addition to SHC, that remain to be de- 
scribed. A novel, widely expressed tyrosine phos- 
phatase with two SH2 domains has recently been 
isolated and is being characterized. 
A Network of SH2-mediated Interactions 
in Signal Transduction 
The role of SH2 domains in directing the associa- 
tion of signaling proteins with growth factor recep- 
tors has been extensively explored. SH2 domains 
also appear important in the subsequent interac- 
tions of proteins such as GAP and Src with cytoplas- 
mic tyrosine-phosphorylated proteins. In particular, 
the Src SH2 domain may play multiple roles in regu- 
lating c-Src tyrosine kinase activity and in substrate 
recognition. Notably, the SH2 domain of the onco- 
genic Src tyrosine kinase associates with a specific 
subset of the proteins that are phosphorylated by the 
Src kinase domain. These interactions may serve sev- 
eral functions, including protecting these substrates 
from dephosphorylation and promoting the forma- 
tion of signaling complexes. 
Biological Functions of Receptor 
Tyrosine Kinases and Their Targets 
The mechanisms controlling the interactions of 
tyrosine kinases with cytoplasmic signaling pro- 
teins, and the functions of specific signal transduc- 
tion pathways in regulating cell phenotype, are be- 
ing variously investigated. At a molecular level, the 
biophysical and biochemical properties of SH2- 
phosphoprotein complexes are being pursued. The 
effects of specific SH2-containing proteins on cellu- 
lar responses to extracellular signals are under in- 
vestigation. In addition, genetic approaches involv- 
ing Drosophila melanogaster, Caenorhabditis 
elegans, and the mouse are being pursued to define 
the role of these gene products in development. 
Although a plethora of receptor tyrosine kinases 
have been identified, the biological functions of 
most of these are unknown. Dr. Pawson's laboratory 
previously described a mammalian receptor tyro- 
sine kinase, encoded by the elk gene, that is specifi- 
cally expressed in the brain. More recently Dr. Mark 
Henkemeyer demonstrated that a novel receptor ty- 
rosine kinase of the eph/elk family, termed nuk, is 
segmentally expressed during the early develop- 
ment of the mouse central nervous system and may 
therefore be involved in patterning of the nervous 
system. The function of this gene and its product is 
under investigation, using both genetic and bio- 
chemical approaches. 
Dr. Pawson is a Senior Scientist at the Samuel 
Lunenfeld Research Institute of Mount Sinai Hos- 
pital, Toronto, and Professor of Molecular and 
Medical Genetics at the University of Toronto. 
Articles 
Koch, C.A., Moran, M.F., Anderson, D., Liu, X.Q., 
Mbamalu, G., and Pawson, T. 1992. Multiple 
SH2-mediated interactions in v-5rc-transformed 
cells. Mol Cell Biol 12:1366-1374. 
McGlade, C.J., Ellis, C., Reedijk, M., Anderson, D., 
INTERNATIONAL RESEARCH SCHOLARS 525 
