Class II phosphoinositide 3-kinase C2alpha: what we learned so far

Abstract

More than fifteen years after the first identification of a class II isoform of phosphoinositide 3-kinase (PI3K) in Drosophila melanoǵaster this subfamily remains the most enigmatic among all PI3Ks. What are the functions of these enzymes? What are their mechanisms of activation? Which downstream effectors are specifically regulated by these isoforms? Are class I and class II PI3Ks redundant or do they control different intracellular processes? And, more important, do class II PI3Ks have a role in human diseases? The recent increased interest on class II PI3Ks has started providing some answers to these questions but still a lot needs to be done to completely uncover the contribution of these enzymes to physiological processes and possibly to pathological conditions. Here we will summarise the recent findings on the alpha isoform of mammalian class II PI3Ks (PI3K-C2α ) and we will discuss the potential involvement of this enzyme in human diseases.

Figure 1.

PI3K-C2α structure. Schematic representation of the protein domains present on PI3K-C2α and descriptive comparison with the other PI3K isoforms.

Figure 2.

Schematic representation of exocytosis and GLUT4 translocation. (A) In a very simplistic model, exocytosis involves the initial recruitment of the granules to the plasma membrane, followed by their docking, priming and finally fusion. Different syntaxins and SNAPs can be involved in this process, according to the specific cellular system. (B) GLUT4 translocation also involves recruitment of GLUT4-containing vesicles to the plasma membrane, docking and fusion.

Figure 3.

Involvement of PI3K-C2α in exocytosis and GLUT4 translocation. (A) Upon insulin stimulation, PI3K-C2α is recruited to the plasma membrane where it generates a pool of Ptdlns3P which, in a mechanism still not defined, participates to GLUT4 translocation. (B) During neurosecretion, PI3K-C2α (which is associated to the granules) generates Ptdlns3P on the granules. (CD) PI3K-C2α is also required for insulin granules exocytosis. Whether the enzyme translocates from the cytoplasm to the plasma membrane upon cellular stimulation (C) or it is associated to the granules (D) remains to be defined.

Figure 4.

Co-operative roles of class I PI3Ks and PI3K-C2α. (A) Class I PI3Ks and PI3K-C2α are both required for full GLUT4 translocation and glucose transport in muscle cells. (B) Members of the class I subfamily and PI3K-C2α have been demonstrated to be involved in the process of insulin secretion. (C) Activation of class I PI3K downstream of the A isoform of the insulin receptor (IR-A) is required for transcription of the insulin gene whereas activation of PI3K-C2α downstream of IR-B controls transcription of β-GK [26,33].