Endocrine Abstracts

Phosphoinositide 3-kinase γ (PI3Kγ) is key to inflammation, allergy, cardiovascular, and metabolic disease.¹ PI3Kγ is a drug target in chronic inflammation, rheumatoid arthritis,² atherosclerosis³ and allergic responses.^4,5 Localized, PI3Kγ-mediated PtdIns (3,4,5)P₃ production⁵, and a distinct role of Ras selectively activating the p84–PI3Kγ-complex, can modulate PI3Kγ activation in a cell-specific way. Moreover, PI3Kγ can be controlled by upstream kinases such as protein kinase A (PKA)⁶ and PKC⁷, depending on target tissues. Obesity is associated with chronic, low-grade inflammation, which involves PI3Kγ-dependent leukocyte recruitment. Interestingly, PI3Kγ-null mice display attenuated high fat diet-induced obesity, fatty liver and insulin resistance. The lean PI3Kγ-null mouse phenotype can be explained by increased thermogenesis, but was found to be independent of functional PI3Kγ in the hematopoietic compartment⁸. In summary, PI3Kγ can be (re-)defined as an integrating node of G protein-coupled receptor signaling, which is also accessible to alternative input signals downstream of protein kinases. PI3Kγ responds to metabolic and inflammatory stress, and provides modes of modulation of metabolic disease, inflammation and cardiovascular disease. For reviews see⁹.

References: 1. Wymann & Schneiter. Nat Rev Mol Cell Biol 2008 9 162.

2. Camps M et al. Nat Med 11 936.

3. Fougerat, A et al. Circulation 117 1310–1317.

4. Laffargue et al. Immunity 2002 16 441; Collmann et al. JACI 2013 132 959.

5. Bohnacker T et al. Sci Signal 2 ra27.

6. Perino A et al. Mol Cell 42 84.

7. Walser et al. PLoS Biol 2013 11 e1001587.

8. Becattini B et al. PNAS 108 E854.

9. Marone R et al. BBA 2008 1784 159; Wymann. Subcell Biochem 2012 58 111.