Essential Cell Biology 5th edition

560 CHAPTER 16 Cell Signaling
Figure 16–31 Ras activates a MAP-kinase
signaling module. The Ras protein, activated
by the process shown in Figure 16–30, activates
a three-kinase signaling module, which relays
the signal onward. The final kinase in the
module, MAP kinase, phosphorylates various
downstream signaling or effector proteins.
plasma membrane
GTP
activated Ras
protein
activated MAP kinase kinase kinase
ATP
ADP
P P
activated MAP kinase kinase
EXTRACELLULAR SPACE
CYTOSOL
ATP
ADP
P P
activated MAP kinase
ATP
ADP
P P P P
protein X protein Y transcription transcription
regulator A regulator B
CHANGES IN PROTEIN ACTIVITY
CHANGES IN GENE EXPRESSION
In its active state, Ras initiates a phosphorylation cascade in which a series
of serine/threonine kinases phosphorylate and activate one another in
sequence, like an intracellular game of dominoes. This relay system, which
carries the signal from the plasma membrane to the nucleus, includes a
three-kinase module called the MAP-kinase signaling module, in honor
of the final enzyme in the chain, the mitogen-activated protein kinase,
or MAP kinase. (As we discuss in Chapter 18, mitogens are extracellular
signal molecules that stimulate cell proliferation.) In this pathway, outlined
in Figure 16–31, MAP ECB5 kinase e16.34/16.31 is phosphorylated and activated by
an enzyme called, logically enough, MAP kinase kinase. This protein is
itself switched on by a MAP kinase kinase kinase (which is activated by
Ras). At the end of the MAP-kinase cascade, MAP kinase phosphorylates
various effector proteins, including certain transcription regulators, altering
their ability to control gene transcription. The resulting change in the
pattern of gene expression may stimulate cell proliferation, promote cell
survival, or induce cell differentiation: the precise outcome will depend
on which other genes are active in the cell and what other signals the
cell receives. How biologists unravel such complex signaling pathways is
discussed in How We Know, pp. 563–564.
Before Ras was discovered in normal cells, a mutant form of the protein
was found in human cancer cells. The mutation inactivates the
GTPase activity of Ras, so that the protein cannot shut itself off, promoting
uncontrolled cell proliferation and the development of cancer. About
30% of human cancers contain such activating mutations in a Ras gene;
of the cancers that do not, many have mutations in genes that encode
proteins that function in the same signaling pathway as Ras. Many of the
genes that encode normal intracellular signaling proteins were initially
identified in the hunt for cancer-promoting oncogenes (discussed in
Chapter 20).
RTKs Activate PI 3-Kinase to Produce Lipid Docking Sites
in the Plasma Membrane
Many of the extracellular signal proteins that stimulate animal cells to
survive and grow, including signal proteins belonging to the insulin-like