The Role of Phosphoinositide 3-Kinase Signaling in Intestinal Inflammation
Figure 1
(a) domain structure of the catalytic subunits of the class 1 PI3-Kinases. Three genes PIK2CA, PIK3CB, and PIK3CD code for the class 1A, p110α, β, and δ isoforms of PI3-K. They have an N-terminal p85 binding domain, a C-terminal catalytic domain, a ras binding domain, a C2 (PKC homology domain), and a phosphatidylinositol kinase homology (PIK) domain. Class 1B is a heterodimer composed of either a p101 or PIKAP (PI3-Kγ adapter protein of 87 kDa) regulatory subunit and a catalytic p110 subunit. GPCRs activate PI3-K through interactions with Gβ [9]. The catalytic p110γ subunit has significant sequence homology to class 1A catalytic subunits; however, its regulatory subunits, p101 and p87, are different from p85. (b) class 1A and class 1B phosphatidylinositol 3-kinases are activated downstream of toll/IL-1 receptors in myeloid cells, and selective isoform-specific inhibitors have been developed. Binding of LPS to CD14 likely induces PI5-kinase to generate PIP2 downstream of integrin β2 (CD11) signaling [10]. LPS/CD14 interaction regulates steady state levels of PIP2 at the plasma membrane and the localization of the MAL adaptor protein. MAL facilitates the TIR-mediated recruitment of the MyD88 adaptor. Tyrosine phosphorylation by a src-related kinase on the TIR domain of MAL/MyD88 or other TLR4 adaptor serves to recruit SH2 containing protein p85, the PI3-K regulatory sub-unit. The catalytic subunits of PI3-K, p110, α, β and δ and γ isoforms mediate the phosphorylation of PIP2 to PIP3. Downstream of the IL-1 receptor, a ras-dependent pathway to the activation of class 1B, PI3-Kinase γ isoform, has recently been reported, associated with myeloid cell trafficking tumor growth and progression [8]. IC-87114 is the first selective PI3-Kδ inhibitor. This selectivity was unexpected given that the residues that line the ATP binding pocket of class 1 PI3-Ks are highly conserved. AS-604850 and AS-605240 are selective, ATP-competitive inhibitors of the PI3-Kγ isoform shown to inhibit intestinal inflammation in murine colitis models.
