The emerging mechanisms of isoform-specific PI3K signalling

Abstract

Phosphoinositide 3-kinases (PI3Ks) function early in intracellular signal transduction pathways and affect many biological functions. A further level of complexity derives from the existence of eight PI3K isoforms, which are divided into class I, class II and class III PI3Ks. PI3K signalling has been implicated in metabolic control, immunity, angiogenesis and cardiovascular homeostasis, and is one of the most frequently deregulated pathways in cancer. PI3K inhibitors have recently entered clinical trials in oncology. A better understanding of how the different PI3K isoforms are regulated and control signalling could uncover their roles in pathology and reveal in which disease contexts their blockade could be most beneficial.

Transcription factor ATF3 mediates the radioresistance of breast cancer

“…The PI3K/Akt pathway is involved in many cellular functions, including protein synthesis, cell cycle progression, cell survival, cell apoptosis, angiogenesis and drug resistance 9. Multiple biological processes, such as cell proliferation, cell metabolism and cell survival, are all regulated by Akt 10.…”

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

“…(8,12) The phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate the 3 0 -hydroxyl group on the inositol ring of phosphatidylinositol. (13)(14)(15) Based on the sequence similarity, composition of the subunits, and substrate specificity, the PI3Ks are divided into three classes: class I, II, and III PI3Ks. Class I PI3K is activated in response to a variety of extracellular stimuli and generates the second messenger phosphatidylinositol-3,4,5-triphosphate (PI-3,4,5-P 3 ) as a result of the phosphorylation of PI-4,5-P 2 , whereas class II and III PI3Ks are constitutively activated and generate PI-3-P. Class I PI3K is a heterodimer of the regulatory and catalytic subunits, and the regulatory subunit is required for the stability as well as kinase activity of the catalytic subunit.…”

“…Class IA PI3K regulates a variety of physiological processes including cell proliferation, survival, migration, and metabolism. (14,15) Class IA PI3K is also required in the immune system for the development and antibody production of B cells, proliferation of T cells, and degranulation of mast cells. (19,20) In certain pathological conditions such as cancer and autoimmune disease, class IA PI3K is hyperactivated and is shown to have an important role in the onset and development of the diseases, suggesting that inhibitors of class IA PI3K may have therapeutic effects in these conditions.…”

“…(19,20) In certain pathological conditions such as cancer and autoimmune disease, class IA PI3K is hyperactivated and is shown to have an important role in the onset and development of the diseases, suggesting that inhibitors of class IA PI3K may have therapeutic effects in these conditions. (14,15) PI3K is known to be stimulated by M-CSF and integrin a v b 3 , both of which are crucial for osteoclast function. (8,9) In vitro inhibitor experiments suggest that PI3K is involved in the differentiation (21) and the bone-resorbing activity (22,23) of osteoclasts, but the level of PI-3,4,5-P 3 has not been quantitated in osteoclasts, and the in vivo function of PI3K in osteoclasts has also not been elucidated.…”

Opposing roles of the oncogene Akt isoforms in tumour progression: is there a dark side to Akt pathway inhibition?

“…Oncogenic mutations in the phosphoinositide (PI) 3-kinase (PI3-K) pathway lead to hyperactivation of all three Akt isoforms [27]. Akt can be activated by steroid hormones or growth factors, downstream of constitutively active Ras and Src pathways [18].…”