Abstract
The class IA isoforms of phosphoinositide 3-kinase (p110alpha, p110beta and p110delta) often have non-redundant functions in a given cell type. However, for reasons that are unclear, the role of a specific PI3K isoform can vary between cell types. Here, we compare the relative contributions of PI3K isoforms in primary and immortalised macrophages. In primary macrophages stimulated with the tyrosine kinase ligand colony-stimulating factor 1 (CSF1), all class IA PI3K isoforms participate in the regulation of Rac1, whereas p110delta selectively controls the activities of Akt, RhoA and PTEN, in addition to controlling proliferation and chemotaxis. The prominent role of p110delta in these cells correlates with it being the main PI3K isoform that is recruited to the activated CSF1 receptor (CSF1R). In immortalised BAC1.2F5 macrophages, however, the CSF1R also engages p110alpha, which takes up a more prominent role in CSF1R signalling, in processes including Akt phosphorylation and regulation of DNA synthesis. Cell migration, however, remains dependent mainly on p110delta. In other immortalised macrophage cell lines, such as IC-21 and J774.2, p110alpha also becomes more prominently involved in CSF1-induced Akt phosphorylation, at the expense of p110delta.These data show that PI3K isoforms can be differentially regulated in distinct cellular contexts, with the dominant role of the p110delta isoform in Akt phosphorylation and proliferation being lost upon cell immortalisation. These findings suggest that p110delta-selective PI3K inhibitors may be more effective in inflammation than in cancer.
Highlights
Class IA phosphoinositide 3-kinases (PI3Ks) are heterodimers consisting of a catalytic subunit (p110α, p110β or p110δ) in complex with one of five regulatory subunits
We found that some responses in a given cell type can be shared by all PI3K isoforms, whereas other functions are isoformspecific
Inactivation of class IA PI3K isoforms in macrophages To pharmacologically interfere with the activity of PI3K isoforms in wild-type (WT) bone marrow macrophages (BMMs), we used the small molecule inhibitors PW12, TGX155 and IC87114, which have
Summary
Class IA phosphoinositide 3-kinases (PI3Ks) are heterodimers consisting of a catalytic subunit (p110α, p110β or p110δ) in complex with one of five regulatory subunits (collectively called the ‘p85s’). We and others have presented evidence that the class IA PI3K isoforms often exert distinct biological roles downstream of specific receptors in various cell types. Evidence for such non-redundancy at the cellular level was obtained by microinjection of PI3K-isoform-specific antibodies in cells (Bénistant et al, 2000; Hooshmand-Rad et al, 2000; Leverrier et al, 2003; Roche et al, 1994; Sawyer et al, 2003; Vanhaesebroeck et al, 1999; Windmiller and Backer, 2003; Yip et al, 2004). Overexpression of PI3Ks in avian fibroblasts shows remarkable differences in signalling and biological output between different PI3K isoforms (Denley et al, 2007; Kang et al, 2006)
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