CONTROL OF CELL GROWTH AND DIFFERENTIATION 
BY TRANSFORMING GROWTH FACTOR-/? 
Joan Massague, Ph.D., Investigator 
The proliferation of cells is controlled by a bal- 
ance of positive and negative signals. The machinery 
that conveys growth inhibitory signals is similar in 
design to that which signals cell growth. Both in- 
volve factors that circulate between cells and mem- 
brane growth factor receptors that are coupled to 
signal transduction circuitry inside the cell. The sig- 
nals carried by growth-promoting factors have been 
extensively studied for the past two decades. The 
growth inhibitors, however, have come to the atten- 
tion of Dr. Massague only recently. Yet they include 
some of the most widespread and versatile regula- 
tors of cell growth and differentiation. Some are im- 
plicated in processes of development and tissue re- 
pair, and their study may illustrate ways to constrain 
the unrestricted growth of cancer cells. In addition, 
given their multifunctional nature, they may serve 
to dissect the signaling networks that are coupled to 
regulation of cell cycle progression, differentiation, 
senescence, and death. 
Multifunctional Growth Inhibitors 
and Their Receptors 
Transforming growth factor-/? (TGF-jS) is a proto- 
typic growth inhibitory polypeptide. It belongs to a 
large family of growth and differentiation factors 
that also includes the activins, the bone morphoge- 
netic proteins (BMPs), the Miillerian inhibiting sub- 
stance (MIS), and others. The evolutionary conser- 
vation of these factors is unusually strict, and they 
are broadly multifunctional. For example, TGF-/3 
can inhibit cell proliferation, regulate cell differen- 
tiation, and influence supracellular organization by 
controlling cell adhesion, migration, and extracel- 
lular matrix formation. 
Over the past year, research in Dr. Massague's lab- 
oratory has centered on identifying and cloning re- 
ceptors for TGF-|8 and related factors. Each of these 
factors binds to various classes of membrane pro- 
teins that can be visualized by receptor affinity- 
labeling assays. One class consists of transmembrane 
receptors with a protein-serine/threonine kinase 
domain in the cytoplasmic region. One member of 
this class binds TGF-jS, whereas others bind activin. 
It is anticipated that additional members of this fam- 
ily yet to be cloned bind the other TGF-/3-related 
factors, BMPs and MIS. Like the factors they bind, 
these receptors exist in many isoforms, each proba- 
bly representing a discrete adaptation to achieve op- 
timal control of cell functions. 
In contrast to the large class of growth factor re- 
ceptors with protein-tyrosine kinase activity, the 
serine/threonine kinase TGF-/3 receptor requires an- 
other TGF-|8-binding component to signal. Dr. Mas- 
sague and his colleagues are examining the hypoth- 
esis that the serine/threonine kinase receptors 
signal as part of heteromeric receptor complexes. 
Another recently cloned TGF-;6 receptor type is 
interesting for other reasons. This protein, betagly- 
can, is thought to act as a helper of the signaling 
receptors. Rather than mediating cell responses di- 
rectly, betaglycan appears to act as a regulator of 
cell access to TGF-/3 by either presenting this factor 
to the signaling receptors or storing it for later use 
by the cell. The structure of betaglycan is unusual 
for a growth factor-binding protein: it is a mem- 
brane-anchored proteoglycan that binds TGF-|8 
through its core protein. Work is under way to map 
the portion of this molecule that binds TGF-|8 and to 
test its ability as a modulator of TGF-|8 activity. 
The cloning of these genes makes it possible to 
explore in detail their structural and functional 
properties and to identify additional components of 
the TGF-;8 signal transduction system. Furthermore 
it should now be possible to determine to what ex- 
tent the genetic loss of TGF-|8 receptors might cause 
loss of constraint in cell proliferation and contribute 
to oncogenic transformation. (A grant from the Na- 
tional Institutes of Health provided support for the 
project described above.) 
Coupled Control of Cell Proliferation 
and Differentiation by TGF-/3 
By lengthening Gj phase in the cell cycle, TGF-/3 
can restrict or even arrest cell proliferation. Nor- 
mally this growth inhibitory effect is reversible and 
ends upon removal of TGF-/3 from the medium. 
Growth inhibition might become permanent, how- 
ever, if slow cell cycle progression induced by 
TGF-/3 facilitated cell commitment to terminal dif- 
ferentiation. Often cells that are competent to dif- 
ferentiate remain undifferentiated while exposed to 
proliferative stimuli and undergo differentiation if 
mitogenic stimulation passively subsides. Mitogens 
retain myoblasts in a proliferative state that 
interferes with the ability of MyoDl and related 
transcription factors to initiate differentiation. How- 
ever, myogenic differentiation in developing tissues 
occurs in environments where mitogens presum- 
ably abound, and differentiation in these tissues 
might depend on factors such as TGF-jS that can ac- 
tively override the inhibitory effect of mitogens. 
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