Regulation of inflammation and tumorigenesis by the TIPE family of phospholipid transfer proteins

Abstract

The TIPE (tumor necrosis factor-α-induced protein 8-like) family are newly described regulators of immunity and tumorigenesis consisting of four highly homologous mammalian proteins: TNFAIP8 (tumor necrosis factor-α-induced protein 8), TIPE1 (TNFAIP8-like 1, or TNFAIP8L1), TIPE2 (TNFAIP8L2) and TIPE3 (TNFAIP8L3). They are the only known transfer proteins of the lipid secondary messengers PIP2 (phosphatidylinositol 4,5-bisphosphate) and PIP3 (phosphatidylinositol 3,4,5-trisphosphate). Cell-surface receptors, such as G-protein-coupled receptors and receptor tyrosine kinases, regulate inflammation and cancer via several signaling pathways, including the nuclear factor (NF)-κB and phosphoinositide-3 kinase (PI3K) pathways, the latter of which is upstream of both Akt and STAT3 activation. An expression analysis in humans demonstrated that the TIPE family is dysregulated in cancer and inflammation, and studies both in mice and in vitro have demonstrated that this family of proteins plays a critical role in tumorigenesis and inflammatory responses. In this review, we summarize the current literature for all four family members, with a special focus on the phenotypic manifestations present in the various knockout murine strains, as well as the related cell signaling that has been elucidated to date.

Figure 1

The TIPE family of proteins regulates a wide array of cellular functions. In this figure and caption, 'TIPE' indicates any TIPE family member. Members of the TIPE family of proteins exert a variety of regulatory functions by acting as phospholipid transfer proteins. Specifically, TIPE3 appears to potentiate PI3K signaling, although all family members potentiate signaling downstream of PI3K to some extent. The TIPE family also appears to act as a negative regulator of signaling by directly binding to specific targets, such as Rac1. PI3K, phosphoinositide-3 kinase; TIPE, tumor necrosis factor-α-induced protein 8-like.