Biomedical Engineering Reference
In-Depth Information
networks (Cantley 2002, Andrews
et al.
2007, Hawkins and Stephens 2007).
Members of class II PI3K consist of only a p101 regulatory subunit and a p110γ
catalytic subunit. Class III PI3K consists of a single member, vacuolar protein-
sorting defective 34 (Vps34), which functions for cellular membrane trai cking
vesicles from the Golgi apparatus to the vacuole. Vps34 was also found to regulate
mammalian target of rapamycin (mTOR) activity in response to amino acid
availability and nutrient starvation (Cantley 2002). Recent studies have shown that
PI3Kγ and δ are expressed predominantly, although not exclusively, in leukocytes
and gene targeting experiments indicated that these two enzymes are involved
in innate and adaptive immune responses. In particular, PI3Kγ functions as a
chemokine sensor regulating leukocyte migration. Furthermore, this enzyme is
found in vessels, in both smooth muscle and endothelial cells, and participates
in the inl ammatory process by enhancing neutrophil adhesion and subsequent
transendothelial migration, then extravasation (Barberis and Hirsch 2008).
Most of the ligands to activate PI3Kγ are involved in the regulation of gene
expression, secretion, adhesion, migration, and contraction in multiple cell types
in the immune system and vasculature (Hawkins and Stephens 2007). More
specii cally, PI3Ks and the downstream serine/threonine kinase Akt regulate
cellular activation, inl ammatory responses, chemotaxis, cell metabolism,
cytoskeletal rearrangements, and apoptosis (Hirsch
et al.
2000, Williams
et al.
2006, Andrews
et al.
2007, Manning and Cantley 2007). Signaling proteins with
pleckstrin homology (PH) domains accumulate at sites of PI3K activation by directly
binding to PIP2 or PIP3. h e interaction of PH domains on signaling proteins
with PIP2 or PIP3 can modulate signaling and the intracellular localization of the
signaling protein. Some examples of signaling proteins that interact with PIP2
and/or PIP3 include phosphoinositide-dependent kinase-1 (PDK1), PDK2, and
Akt. PDK activates Akt by phosphorylation of h r308 and Ser473. h e activated
Akt results in phosphorylation of a host of other proteins that modulates cell cycle
entry, growth, and survival by regulating an array of specii c gene expression, in
particular to activate NF-κB to modulate adhesion molecule gene expression (Fry
1994, Engelman
et al.
2006, Manning and Cantley 2007).
Nuclear Factor Kappa-B (NF-
k
B)
Members of the NF-κB family of transcription factors (TFs) regulate expression
of a large number of genes involved in immune responses, inl ammation, cell
survival, and cancer. NF-κB is rapidly activated in response to various stimuli,
including cytokines, infectious agents, and radiation-induced DNA damages
(Barnes and Karin 1997, Hacker and Karin 2006). First identii ed as an expression
regulator of the kappa light-chain gene in murine B lymphocytes but subsequently
found in many dif erent cells, NF-κB is a heterodimeric (p65, also called RelA,
with p50, p52 or other subunits such as Rel, RelB, v-rel and p52, respectively),
