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Fig. 4.1
Protein:protein interactions and signaling pathways linked to the P2Y
2
receptor.
Activation of the G
q
-coupled P2Y
2
receptor (P2Y
2
R) stimulates phospholipase C-dependent for-
mation of the second messengers IP
3
and diacylglycerol, which stimulate release of calcium from
intracellular stores and activation of protein kinase C, respectively. The P2Y
2
R also contains an
RGD integrin-binding domain that interacts with integrins (
5
) and enables activa-
tion by nucleotides of G
o
and G
12
proteins. The RGD domain is necessary for P2Y
2
R-mediated
chemotaxis, actin stress fiber formation, and coupling to signaling pathways involving RhoA
and Rac GTPases. Two consensus SH3 binding sites (PXXP) in the C-terminal tail of the P2Y
2
receptor bind directly to Src upon receptor activation and mediate Src-dependent co-localization
and transactivation of growth factor receptors that are required for up-regulation of cell adhe-
sion/chemotactic proteins (e.g., VCAM-1). The P2Y
2
R also can stimulate metalloprotease activity
leading to the cleavage of membrane associated proteins. Abbreviations used: AA, arachidonic
acid; ADAM, a disintegrin and metalloprotease family; ADAM10, the Kuz enzyme; ADAM 17 or
TACE, tumor necrosis factor-
α
β
3
and
α
β
V
V
converting enzyme; AP-1, activator protein-1; APP, amyloid pre-
cursor protein; ATP, adenosine 5
-triphosphate; Ca
2+
, calcium ion; c-fos, the cellular counterpart
of oncogene v-
fos;
cPLA
2
, cytosolic phospholipase A2; DAG, diacylglycerol; ELK, nuclear tran-
scription factor E-26-like protein; ERK, extracellular-signal regulated kinase; Grb2, growth factor
receptor binding protein 2; IP
3,
inositol-1,4,5-trisphosphate; JNK, Jun kinase; MCP-1, monocyte
chemoattractant protein-1; MEK, MAP/ERK kinase; MEKK1, MAP kinase kinase kinase 1; NF-
kB, nuclear factor kB; p90RSK, 90 kDa ribosomal S6 kinase; PGE2, prostaglandin E2; PKC,
protein kinase C; Pyk2, Proline-rich tyrosine kinase; PLC, phospholipase C; PXXP, Src homol-
ogy 3 binding sites; Raf, rapidly accelerated fibrosarcoma; Ras, superfamily of small GTPases;
RGD, arginine-glycine-aspartic acid; sAPP
α
, a soluble, non-amyloidogenic N-terminal fragment
of APP; Shc, an adaptor protein; SOS, Ras-specific nucleotide exchange factor Son of sevenless;
Src, a tyrosine kinase; UTP, uridine 5
-triphosphate; VCAM-1, vascular cell adhesion molecule-1
α
Recent studies suggest that inflammation associated with atherosclerotic lesion
development in brain microvessels can contribute to Alzheimer's disease [3, 84],
and may be a factor in the failure to eliminate amyloidogenic A
β
peptide from
aging human brain [89]. Moreover, A
accumulation promotes cerebrovascular
inflammation [84], most likely due to increased adherence of blood monocytes
β
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