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J Biol Chem, Vol. 274, Issue 42, 30169-30181, October 15, 1999
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From the During the past decade, our knowledge of
molecular mechanisms involved in growth factor signaling has
proliferated almost explosively. However, the kinetics and control of
information transfer through signaling networks remain poorly
understood. This paper combines experimental kinetic analysis and
computational modeling of the short term pattern of cellular responses
to epidermal growth factor (EGF) in isolated hepatocytes. The
experimental data show transient tyrosine phosphorylation of the EGF
receptor (EGFR) and transient or sustained response patterns in
multiple signaling proteins targeted by EGFR. Transient responses
exhibit pronounced maxima, reached within 15-30 s of EGF stimulation
and followed by a decline to relatively low (quasi-steady-state)
levels. In contrast to earlier suggestions, we demonstrate that the
experimentally observed transients can be accounted for without
requiring receptor-mediated activation of specific tyrosine
phosphatases, following EGF stimulation. The kinetic model predicts how
the cellular response is controlled by the relative levels and activity
states of signaling proteins and under what conditions activation
patterns are transient or sustained. EGFR signaling patterns appear to
be robust with respect to variations in many elemental rate constants
within the range of experimentally measured values. On the other hand,
we specify which changes in the kinetic scheme, rate constants, and
total amounts of molecular factors involved are incompatible with the experimentally observed kinetics of signal transfer. Quantitation of
signaling network responses to growth factors allows us to assess how
cells process information controlling their growth and differentiation.
Department of Pathology, Anatomy and Cell
Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 and the ¶ A. N. Belozersky Institute of Physico-Chemical Biology,
Moscow State University, Moscow 119899, Russia
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