Biological Regulation by Protein Phosphorylation
Second Messenger
An intracellular molecule, generated by the cell in response to an extracellular signal
(frst messenger), which triggers a biochemical cascade leading to a change in the
Function or phenotype oF the cell.
The biological activity oF many proteins is modulated by the phosphorylation oF
specifc sites within the protein. Protein kinases catalyze the transFer oF a phosphate
group to the protein, while protein phosphatases remove the phosphate group.
This reversible modifcation is utilized by the cell to dynamically regulate proteins
that are involved in almost all cellular Functions. Protein phosphorylation plays a
particularly prominent role in the transduction oF extracellular signals. A hormone,
neurotransmitter, or growth Factor binds to its cell surFace receptor and may
directly or indirectly activate a protein kinase (or phosphatase) inside the cell, which
leads to changes in the phosphorylation states oF key regulatory proteins. This
cascade oF events ultimately results in a Functional or phenotypic cellular response
(e.g. contraction, release oF neurotransmitter, changes in metabolism, or altered
gene expression).
Importance of Protein Phosphorylation in
Biological Regulation
Protein phosphorylation is one oF the
most common posttranslational modif-
cations to occur in eukaryotic cells. It
has been estimated that
30% oF pro-
teins encoded by the human genome are
phosphorylated at one or more sites. Phos-
phorylation and dephosphorylation is a
Fundamental molecular switch used by
cells to control the activity oF a variety oF
cellular proteins, which in turn regulates a
vast array oF cellular Functions. The types
oF proteins known to undergo reversible
phosphorylation include metabolic en-
zymes, cytoskeletal proteins, transcription
Factors, ion channels, and cell surFace
receptors. Protein phosphorylation is par-
ticularly prominent in signal-transduction
processes. A cell can rapidly respond to
a biological signal by phosphorylating key
intracellular molecules thereby initiating a
cascade oF events resulting in a change in a
physiological property such as cell motility,
release oF neurotransmitters, modulation
oF ion fluxes or alteration in gene expres-
sion. Because oF the prominent role oF
this reversible and tightly coupled protein-
modiFying process, dysregulated protein
phosphorylation can contribute to the
pathogenesis oF human disease.
The phosphorylation state oF a particu-
lar protein is controlled by specifc protein
kinases and phosphoprotein phosphatases
(±ig. 1). Protein kinases are enzymes that
transFer the
-phosphate From a nucle-
oside triphosphate (usually ATP) to an
amino acid side chain oF the substrate pro-
tein. Structural studies have shown that, in
occur within the active site and directly
aFFect substrate binding. Phosphorylation
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