Abstract
The phosphatidylinositol 3-kinase (PI3K) pathway is a critical regulator of many cellular processes including cell survival, growth, proliferation and motility. Not surprisingly therefore, the PI3K pathway is one of the most frequently mutated pathways in human cancers. In addition to their canonical role as part of the PI3K holoenzyme, the class IA PI3K regulatory subunits undertake critical functions independent of PI3K. The PI3K regulatory subunits exist in excess over the p110 catalytic subunits and therefore free in the cell. p110-independent p85 is unstable and exists in a monomer-dimer equilibrium. Two conformations of dimeric p85 have been reported that are mediated by N-terminal and C-terminal protein domain interactions, respectively. The role of p110-independent p85 is under investigation and it has been found to perform critical adaptor functions, sequestering or influencing compartmentalisation of key signalling proteins. Free p85 has roles in glucose homeostasis, cellular stress pathways, receptor trafficking and cell migration. As a regulator of fundamental pathways, the amount of p110-independent p85 in the cell is critical. Factors that influence the monomer-dimer equilibrium of p110-independent p85 offer additional control over this system, disruption to which likely results in disease. Here we review the current knowledge of the structure and functions of p110-independent class IA PI3K regulatory subunits.
Highlights
Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinases that catalyse the transfer of the γ-phosphate group of ATP to the D3 position of phosphoinositides
C-terminal dimers are instigated by phosphorylation on a conserved tyrosine residue in the iSH2 region; Tyr607 for p85α. p85α is phosphorylated downstream of the insulin receptor at Tyr607 [40] and we have found that it is directly phosphorylated by the non-receptor tyrosine kinase (RTK) ACK [41]
As part of the PI3K heterodimer the regulatory subunits mediate signalling through the PI3K pathway
Summary
Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinases that catalyse the transfer of the γ-phosphate group of ATP to the D3 position of phosphoinositides. P85 has been shown to bind active Cdc42 [78] but it is unknown which isoforms constitute the p85 dimer that functions in the Cdc42/MKK4/JNK signalling node These findings detail an additional mechanism by which p110-free p85α negatively regulates insulin signalling, further highlighting its dual role in both positive and negative regulation of the insulin response. The requirement for the N-terminal domains of the PI3K regulatory subunits in mediating the p110-independent functions of p85 in the insulin response provides strong evidence for the physiological relevance of C-terminal dimers, in which the N-terminal protein domains are freely accessible. The importance of the PI3K regulatory subunits in receptor down-regulation is evident in cells expressing mutant PDGFR that cannot be phosphorylated at the p85-binding residues (Y740F and Y751F), which despite being internalised failed to be trafficked to the lysosome for degradation [89,90]. The monomer-dimer equilibrium may itself be influenced by favourable interactions with N-terminal domains, such as those to cytoskeleton components, providing a mechanism whereby the cytoskeleton and its regulators could influence other cellular processes
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