plasticity that could explain, at least partially, the 
variability between pathogenic and nonpathogenic 
trophozoites. 
Dr. Orozco is Professor in the Department of 
Experimental Pathology at the Center for Re- 
search and Advanced Studies, National Polytech- 
nic Institute, Mexico City. 
Articles 
Descoteaux, S., Ayala, P., Orozco, E., and Sam- 
uelson, J. 1992. Primary sequences of two P- 
glycoprotein genes of Entamoeba histolytica. 
Mol Biochem Parasitol 54:201-212. 
Orozco, E. 1992. Pathogenesis in amebiasis. Infect 
Agents Dis 1 : 1 9-2 1 . 
INTERACTIONS OF PROTEIN-TYROSINE KINASES WITH THEIR TARGETS 
Tony Pawson, Ph.D., International Research Scholar 
Many of the receptors for the polypeptide hor- 
mones that control cell growth, differentiation, and 
metabolism bind to cell surface receptors with pro- 
tein-tyrosine kinase activity. A distinct class of tyro- 
sine kinases, typified by the c-src gene product, are 
localized entirely within the cell and are implicated 
in a variety of signaling processes. In addition to 
their role in controlling the interactions of normal 
cells, constitutively active variants of tyrosine ki- 
nases are implicated in the development of some 
cancers. Dr. Pawson's laboratory is interested in the 
mechanisms by which tyrosine kinases activate in- 
tracellular signal transduction pathways and thereby 
regulate gene expression, cytoskeletal architecture, 
cell-cell interactions, and cell metabolism. The labo- 
ratory is also investigating the role of protein kinases 
and their targets in the control of vertebrate and in- 
vertebrate development. 
Targets of Tyrosine Kinases Contain 
Src Homology 2 (SH2) Domains 
A growing number of cytoplasmic signaling pro- 
teins contain small noncatalytic domains, termed 
SH2 and SH3. SH2 domains were originally identi- 
fied in nonreceptor tyrosine kinases such as Src, Fps, 
and Abl, and were proposed to play a role in the 
interactions of these kinases with specific sub- 
strates. Subsequently, SH2 domains were detected 
in several signaling proteins that associate with, and 
are phosphorylated by, activated growth factor re- 
ceptors, including Ras GTPase-activating protein 
(GAP), phospholipase C-7 (PLC-7), and phosphati- 
dylinositol (PI) 3'-kinase. 
PI 3'-kinase is a heterodimer composed of an SH2- 
containing, receptor-binding subunit (p85), which 
apparently couples tyrosine kinases to the PI 3'- 
kinase catalytic subunit. The p85 regulatory subunit 
of PI 3'-kinase is one of several SH2-containing pro- 
teins, including Crk, Nek, She, and Sem-5, that lack 
any obvious catalytic domains, and may therefore 
serve as adaptors to link receptor tyrosine kinases to 
specific signaling enzymes that have no intrinsic 
ability to interact with receptors. 
The binding of cytoplasmic signaling proteins to 
activated receptor tyrosine kinases is mediated by 
their SH2 domains. Individual SH2 domains from 
proteins such as PLC-7, GAP, Src, and PI 3'-kinase, 
synthesized in bacteria, bind to specific autophos- 
phorylated growth factor receptors in vitro, al- 
though with different efficiencies. Hence a struc- 
turally and functionally diverse group of enzymes 
are endowed with the capacity to recognize acti- 
vated receptors with high affinity by virtue of their 
common SH2 domains. 
A variety of data indicate that SH2 domains bind 
directly to specific tyrosine-phosphorylated sites lo- 
cated within noncatalytic regions of activated re- 
ceptors. As an example, the kinase-insert region of 
the macrophage colony-stimulating factor (CSF-1) 
receptor, although not essential for receptor kinase 
activity, is both necessary and sufficient for binding 
to PI 3'-kinase, provided that the insert is tyrosine- 
phosphorylated. Although the kinase insert of the 
mouse CSF- 1 receptor becomes autophosphorylated 
at multiple tyrosine residues following CSF-1 stim- 
ulation, binding of the SH2 domains of the p85 
PI 3 -kinase subunit requires phosphorylation of 
Tyr^^\ which lies within a consensus sequence for 
PI 3'-kinase association and is entirely independent 
of autophosphorylation at other sites. 
Such results indicate that SH2 domains recognize 
phosphotyrosine but require a specific surrounding 
amino acid sequence for high-affinity binding. Mu- 
tagenesis of the GAP SH2 domains has implicated an 
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