Inhibitor SourceBook™ Second Edition

Phosphorylation/Dephosphorylation
Mitogen-Activated Protein (MAP) Kinase Inhibitors
The mitogen-activated protein (MAP) kinases are a group
of evolutionarily conserved protein serine/threonine
kinases that are activated in response to a variety of
extracellular stimuli and mediate signal transduction
from the cell surface to the nucleus. They regulate several
physiological and pathological cellular phenomena,
including inflammation, apoptotic cell death, oncogenic
transformation, tumor cell invasion, and metastasis. MAP
kinases, in combination with several other signaling
pathways, can differentially alter the phosphorylation
status of transcription factors in a pattern unique to
a given external signal. Although MAP kinases are
expressed in all cell types, they regulate very specific
biological responses that differ from cell type to cell type.
Four major types of MAP kinase cascades have been
reported in mammalian cells that respond synergistically
to different upstream signals. MAP kinases are part
of a three-tiered phospho-relay cascade consisting of
MAP kinase, a MAP kinase kinase (MEK) and a MAP
kinase kinase kinase (MEKK). Controlled regulation
of these cascades is involved in cell proliferation and
differentiation, whereas unregulated activation of
these MAP kinases can result in oncogenesis. The most
widely studied cascade is that of ERK1/ERK2 MAP
kinases. In the cell, one highly active form of ERK1 or
ERK2 (dual phosphorylated) exists, which exhibits over
1000-fold greater activity than the unphosphorylated
form. At any one time, there may be three low activity
forms of ERKs: one unphosphorylated enzyme, and two
singly phosphorylated forms that contain
phosphate either at a tyrosine or a
threonine residue.
The JNK/SAPK cascade is
activated following exposure
to UV radiation,
heat shock, or
inflammatory
cytokines. The
activation of these
MAP kinases is
mediated by Rac
and cdc42, two
small G-proteins.
Activated cdc42
binds to PAK protein
kinase and activates
it. Activated PAK 65 can
activate MEKK, which in turn phosphorylates SEK/JNKK
and activates it. The active SEK/JNKK phosphorylates
JNK/SAPK (at the TPY motif). The sites of activating
phosphorylation are conserved between ERK and JNK,
however, these sites are located within distinct dual
specificity phosphorylation motifs (TPY for JNK and
TEY for ERK).
The p38 kinase, another member of the MAP kinase
family, bears similarity to the yeast MAPK, Hog-1. It
is activated in response to inflammatory cytokines,
endotoxins, and osmotic stress. It shares about 50%
homology with the ERKs. The upstream steps in its
activation of this cascade are not well defined. However,
downstream activation of p38 occurs following its
phosphorylation (at the TGY motif) by MKK3, a dual
specificity kinase. Following its activation, p38
translocates to the nucleus and phosphoryates ATF-2.
Another known target of p38 is MAPKAPK2 that is
involved in the phosphorylation and activation of heatshock
proteins.
The fourth and least studied mammalian MAP kinase
pathway is big MAP kinase 1 (BMK1), also known as
extracellular signal regulated kinase 5 (ERK5). BMK1
is activated in response to growth factors and stress.
Activation of the BMK1 signaling pathway has not
only been implicated in normal cell survival, cell
proliferation, cell differentiation, but also in
24 Orders Phone 800 854 34 7
Calbiochem • Inhibitor SourceBook
Fax 800 776 0999
Web www.emdbiosciences.com/calbiochem