Cell Regulation by Transforming 
Growth Factors 
Joan Massague, Ph.D. — Investigator 
Dr. Massague is also a member of the Cell Biology and Genetics Program at Memorial Sloan- Kettering 
Cancer Center and Professor of Cell Biology at Cornell University Graduate School of Medical Sciences, 
New York. He received his Ph.D. degree in biochemistry from the University of Barcelona, Spain, and was 
a postdoctoral fellow with Michael Czech at Brown University. He was Assistant and Associate Professor 
of Biochemistry at the University of Massachusetts Medical School before assuming his present position. 
THE proliferation of cells is controlled by a 
balance of positive and negative signals. The 
machinery that conveys growth inhibitory signals 
is similar in design to that which signals cell 
growth. Both involve 1) factors that circulate be- 
tween cells and 2) membrane receptors that are 
coupled to signal transduction circuitry inside 
the cell. The signals carried by growth-promoting 
factors have been extensively studied for the past 
two decades. The growth inhibitors, however, 
have come to the attention of biologists only re- 
cently. Yet they include some of the most wide- 
spread and versatile regulators of cell growth and 
phenotype. Some of them are implicated in pro- 
cesses of development, tissue repair, and recy- 
cling, and their study may show us ways to con- 
strain the unrestricted growth of cancer cells. 
Multifunctional Growth Inhibitors 
and Their Receptors 
Ranking high in the list of growth inhibitors, 
and in our research interests, is the polypeptide 
TGF-(S (transforming growth factor-/?) . In reality, 
TGF-(S represents a large family of growth and dif- 
ferentiation factors that also includes the acti- 
vins, the bone morphogenetic proteins, the 
Miillerian inhibiting substance, and others. The 
evolutionary conservation of these factors is un- 
usually strict, and they are broadly multifunc- 
tional. For example, TGF-)8 can inhibit cell prolif- 
eration, regulate cell differentiation, affect how 
cells organize tissue structures, and perform 
various other functions in cells from virtually 
every lineage. Likewise, other members of the 
family, such as activin and decapentaplegic, are 
involved in body axis formation during embryo 
development. 
Over the past year our research program has 
centered on identifying and isolating genes that 
encode receptors for TGF-(8 and related factors. 
We had previously determined that TGF-|8 binds 
to various types of receptor proteins on the cell 
membrane, and we have recently cloned genes 
for two classes of such receptors. One class com- 
prises receptor membrane proteins that can trig- 
ger a biochemical reaction inside the cell upon 
binding a factor on the outside. The receptors in 
this class probably mediate most cellular re- 
sponses to these factors. Like the factors they 
bind, these receptors exist in many variants, each 
probably representing a discrete adaptation to 
achieve optimal control of cell functions. 
One member of this receptor class binds the 
TGF-/3-related factor activin. The biochemical re- 
action carried out by this receptor is the transfer 
of phosphate from ATP to serine and threonine 
groups present in certain intracellular proteins. 
Phosphorylation of serines and threonines repre- 
sents a significant departure from previously 
known receptor signals. In contrast to the recep- 
tors for activin and TGF-|8, those for growth- 
promoting factors typically trigger phosphoryla- 
tion of tyrosine groups in proteins. Thus the tyro- 
sine phosphorylation signals of mitogens are 
challenged by the serine/threonine phosphoryla- 
tion signals of antimitogens. These findings offer 
new insight into the counteracting signals that 
preserve the normal balance of cell growth. This 
work has been supported by a grant from the Na- 
tional Cancer Institute. 
Receptor Accessory Molecules 
The other TGF-/? receptor class recently cloned 
by our group is interesting for other reasons. This 
protein, called betaglycan, is thought to act as a 
helper of the signaling receptors. Rather than me- 
diate cell responses directly, betaglycan seems to 
regulate the access of cells to TGF-|8 by either 
helping present this factor to the signaling recep- 
tors or storing it for later use by the cell. 
The structure of betaglycan is unusual for a 
growth factor-binding protein. It consists of a 
core protein that carries a large mass of negatively 
charged carbohydrate. TGF-/3 binds the core pro- 
tein, whereas the carbohydrate can bind the so- 
called heparin-binding growth factors. Work is 
under way to map the portion of this molecule 
that binds TGF-jS and to test its ability as a modula- 
tor of TGF-|8 activity. 
With the cloning of these genes, it is now possi- 
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