  The protein-protein interaction (PPI) network is crucial for cellular
information processing and decision-making. With suitable inputs, PPI networks
drive the cells to diverse functional outcomes such as cell proliferation or
cell death. Here we characterize the structural controllability of a large
directed human PPI network comprised of 6,339 proteins and 34,813 interactions.
This allows us to classify proteins as "indispensable", "neutral" or
"dispensable", which correlates to increasing, no effect, or decreasing the
number of driver nodes in the network upon removal of that protein. We find
that 21% of the proteins in the PPI network are indispensable. Interestingly,
these indispensable proteins are the primary targets of disease-causing
mutations, human viruses, and drugs, suggesting that altering a network's
control property is critical for the transition between healthy and disease
states. Furthermore, analyzing copy number alterations data from 1,547 cancer
patients reveals that 56 genes that are frequently amplified or deleted in nine
different cancers are indispensable. Among the 56 genes, 46 of them have not
been previously associated with cancer. This suggests that controllability
analysis is very useful in identifying novel disease genes and potential drug
targets.
