Cell Regulation by Transforming Growth Factors 
ble to explore their properties in detail and to 
identify key pieces of the machinery that transfers 
growth inhibitory signals from the membrane to 
the nucleus. Furthermore, it should be possible 
to determine to what extent the genetic loss of 
TGF-jS receptors might cause loss of constraint in 
cell proliferation and thus incite tumor cell 
outgrowth. 
Cell-Cell Stimulation by Membrane-bound 
Growth Factors 
Paracrine growth factors and polypeptide hor- 
mones are generally synthesized as larger soluble 
precursors that are later fragmented to yield the 
bioactive forms. In a recently found variation of 
this theme, factors such as TGF-a (no structural 
relationship to TGF-jS) are generated from mem- 
brane-anchored proteins rather than from soluble 
precursors. The TGF-a precursor can accumulate 
on the cell membrane and bind to receptors lo- 
cated on the surface of adjacent cells. This inter- 
action can sustain cell-cell adhesion and stimu- 
late DNA replication by cell-cell contact. 
In work supported by a grant from the National 
Cancer Institute, we have shown that generation 
of TGF-a by cleavage of its precursor occurs at 
the cell surface by a highly regulated enzymatic 
system. This system is strongly activated by 
tumor-promoting phorbol esters and growth fac- 
tors via mechanisms involving protein kinase C 
and calcium influx into the cell. Thus the precur- 
sor cleavage process functions as a regulated 
switch between two active forms of the grouT:h 
factor, one membrane-bound and the other diffus- 
ible. The membrane-bound forms could be im- 
portant in tissue development processes whose 
guidance depends on discrete cell-cell interac- 
tions incompatible with the diffusible nature of 
soluble factors. The regulated nature of the pro- 
TGF-a cleavage process renders it susceptible to 
exogenous control with pharmacologic agents. 
Furthermore, it provides a way to identify the 
pieces of the general machinery controlling the 
release of this and other membrane proteins that 
mediate cell-to-cell interaction. 
In this molecular model, a benzene molecule 
(in yellow) is shown buried within the core of 
T4 lysozyme in a cavity created by replacing 
leucine 99 with alanine. The inner dotted form 
represents the van der Waals surface of the ben- 
zene, and the outer envelope, the van der Waals 
surface of the cavity. 
Research and photograph by A. Elisabeth 
Eriksson and Xue-jun Zhang in the laboratory 
of Brian Matthews. 
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