Essential Cell Biology 5th edition

570 CHAPTER 16 Cell Signaling
cyclase, which increases (or decreases) the intracellular concentration
of the second messenger molecule cyclic AMP; others directly
activate the enzyme phospholipase C, which generates the second
messenger molecules inositol trisphosphate (IP 3 ) and diacylglycerol.
• IP 3 opens Ca 2+ channels in the membrane of the endoplasmic reticulum,
releasing a flood of free Ca 2+ ions into the cytosol. The Ca 2+ itself
acts as a second messenger, altering the activity of a wide range of
Ca 2+ -responsive proteins. These include calmodulin, which activates
various target proteins such as Ca 2+ /calmodulin-dependent protein
kinases (CaM-kinases).
• A rise in cyclic AMP activates protein kinase A (PKA), while Ca 2+ and
diacylglycerol in combination activate protein kinase C (PKC).
• PKA, PKC, and CaM-kinases phosphorylate selected signaling and
effector proteins on serines and threonines, thereby altering their
activity. Different cell types contain different sets of signaling and
effector proteins and are therefore affected in different ways.
• Enzyme-coupled receptors have intracellular protein domains that
function as enzymes or are associated with intracellular enzymes.
Many enzyme-coupled receptors are receptor tyrosine kinases
(RTKs), which phosphorylate themselves and selected intracellular
signaling proteins on tyrosines. The phosphotyrosines on RTKs then
serve as docking sites for various intracellular signaling proteins.
• Most RTKs activate the monomeric GTPase Ras, which, in turn, activates
a three-protein MAP-kinase signaling module that helps relay
the signal from the plasma membrane to the nucleus.
• Ras mutations stimulate cell proliferation by keeping Ras (and, consequently,
the Ras–MAP kinase signaling pathway) constantly active
and are a common feature of many human cancers.
• Some RTKs stimulate cell growth and cell survival by activating
PI 3-kinase, which phosphorylates specific inositol phospholipids in
the cytosolic leaflet of the plasma membrane lipid bilayer. This inositol
phosphorylation creates lipid docking sites that attract specific
signaling proteins from the cytosol, including the protein kinase Akt,
which becomes active and relays the signal onward.
• Other receptors, such as Notch, have a direct pathway to the nucleus.
When activated, part of the receptor migrates from the plasma membrane
to the nucleus, where it regulates the transcription of specific
genes.
• Some extracellular signal molecules, such as steroid hormones and
nitric oxide, are small or hydrophobic enough to cross the plasma
membrane and activate intracellular proteins, which are usually
either transcription regulators or enzymes.
• Plants, like animals, use enzyme-coupled cell-surface receptors to
recognize the extracellular signal molecules that control their growth
and development; these receptors often act by relieving the transcriptional
repression of specific genes.
• Different intracellular signaling pathways interact, enabling each cell
type to produce the appropriate response to a combination of extracellular
signals. In the absence of such signals, most animal cells
have been programmed to kill themselves by undergoing apoptosis.
• We are far from understanding how a cell integrates all of the many
extracellular signals that bombard it to generate an appropriate
response.