trans

REVERSIBLE PROTEIN PHOSPHORYLATION 267
Ligand
Gi or Gq – Coupled receptor
Tyrosine kinase
receptor
Catalytic domain
Cytoskeleton Protein kinase Phospholipase Transcription factors Cell cycle
FIGURE 11.8 (See also Color Plate 9) Activation of the MAPK pathway by receptor tyrosine kinases and seven
transmembrane or serpentine receptors. Binding of a ligand to receptor activates guanine nucleotide exchange
factor (GEF) Sos through the adaptor protein Grb2. Sos then activates membrane-bound Ras by exchanging GDP with
GTP. The activated Ras, through an unknown mechanism, recruits and activates MAP3K and thereby the MAPK
module. A scaffold protein, such as Ste5 from the S. cerevisiae mating response pathway, often brings the individual
members of the MAPK module together. Recently, similar scaffold proteins, MP1 and JIP-1, have been discovered
in mammalian cell stress response pathways. The MAPK module can also be activated by signals received through
serpentine receptors. Binding of a ligand to a serpentine receptor activates membrane-anchored heterotrimeric
G-protein. The exchange of GDP with GTP separates G and G subunits. The MAPK module is then recruited to
the free G subunit through additional intermediary proteins. For examples, in S. cerevisiae Ste20, a MAP4K acts to
recruit the MAPK module to G . Activated MAPKs then phosphorylate a variety of cellular substrates.
unphosphorylated state the two lobes of MAPKs
are at a distance that leads to misalignment of
amino acid residues in the active site. Following
dual phosphorylation by MAP kinase kinases
(MAPKK), there is a conformational change in
the activation domain that leads to proper
alignment of residues involved in catalysis.
Each MAPKK is in turn activated by serine/
threonine phosphorylation in subdomain VIII
by MAPKK kinases (MAPKKK).
It is now well established that the threekinase
module (MAPKKK-MAPKK-MAPK) is
used to activate the mammalian and yeast
MAPK signaling pathway. Different sets of
stimuli activate different modules. Various isoforms
have been identified for each member
of these modules. Scaffold proteins that anchor
various components present in a module provide
the specificity of activation of a signaling
pathway. For example, in yeast, the signaling
pathway for mating response uses the scaffold
protein Ste5 which binds the module proteins
Ste11 (MKKK), Ste7 (MKK), and Fus3 (MAPK).
However, in the osmosensing pathway, PBS2
acts both as the scaffold and MAPKK, anchoring
the same MAPKKK (Ste11) but recruiting
BIOCHEMISTRY AND CELL BIOLOGY: PROTOZOA