Research Topic

Human Disorders of PI3K Biology

About this Research Topic

Studies of inherited mutations underlying rare human disorders elucidate genes and pathways of fundamental importance to human health. The phosphoinositide 3-kinase (PI3K) pathway has recently been highlighted as a driver of disease when either hyperactivated or inactivated due to germline mutations. In particular, the class I PI3Ks, which phosphorylate the phosphoinositol-4,5-bisphosphate lipid to produce the phosphoinositol-3,4,5-trisphosphate (PIP3) second messenger, have become the focus of intense investigation in recent years due to germline mutations identified in several diseases affecting the immune system, tissue growth, brain, metabolism, and cancers. Class I PI3Ks are comprised of a complex of two proteins, a catalytic subunit and a regulatory subunit. There are three class IA (activated by tyrosine phosphorylation events) catalytic subunits, p110α, p110β, and p110δ, and these interact with the p85α/p55α/p50α (all from the PIK3R1 gene), p85β, or p55γ regulatory subunit. Class IB (activated by G protein-coupled receptor signaling) PI3K has a single catalytic subunit, p110γ, which interacts with either the p101 or p101 regulatory subunit. Both p110δ and p110γ are expressed predominantly in leukocytes, while the other catalytic subunits are more ubiquitously expressed.

Immunodeficiency disorders have been attributed to both loss- and gain-of-function mutations in the genes encoding p110δ or p85α. There is also now evidence that some of the features caused by p110δ hyperactivation are recapitulated in patients with loss-of-function mutations in the PTEN phosphatase, which functions to dephosphorylate the PIP3 second messenger and suppress PI3K signaling. Very recent data have also emerged indicating pro-inflammatory effects of p110γ inhibition in animals, highlighting a potential negative regulatory function of p110γ predominantly in myeloid cells. Outside the immune system, class I PI3K gene mutations have been found as the cause of a spectrum of rare tissue overgrowth disorders and multi-system syndromes. Integrating knowledge gleaned from these diverse disorders and the wealth of information on fundamental PI3K biology offers the potential to gain a more complete picture of this important pathway and potential effects of its therapeutic manipulation for treatment of a vast array of pathologies.

This Research Topic will provide a comprehensive overview of disorders of PI3K biology and will cover various aspects of the primary immunodeficiency disorder called Activated PI3Kδ Syndrome (APDS), or PASLI disease, caused by mutations in the genes encoding p110δ or p85α. It will also cover the physiological consequences of PTEN deficiency, p110γ inhibition, p85α deficiency, p110δ deficiency, and inherited non-immune overgrowth and metabolic disorders from mutations in PI3K genes.


Keywords: PI3K, Monogenic Disorders, Immunodeficiency, Overgrowth


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

Studies of inherited mutations underlying rare human disorders elucidate genes and pathways of fundamental importance to human health. The phosphoinositide 3-kinase (PI3K) pathway has recently been highlighted as a driver of disease when either hyperactivated or inactivated due to germline mutations. In particular, the class I PI3Ks, which phosphorylate the phosphoinositol-4,5-bisphosphate lipid to produce the phosphoinositol-3,4,5-trisphosphate (PIP3) second messenger, have become the focus of intense investigation in recent years due to germline mutations identified in several diseases affecting the immune system, tissue growth, brain, metabolism, and cancers. Class I PI3Ks are comprised of a complex of two proteins, a catalytic subunit and a regulatory subunit. There are three class IA (activated by tyrosine phosphorylation events) catalytic subunits, p110α, p110β, and p110δ, and these interact with the p85α/p55α/p50α (all from the PIK3R1 gene), p85β, or p55γ regulatory subunit. Class IB (activated by G protein-coupled receptor signaling) PI3K has a single catalytic subunit, p110γ, which interacts with either the p101 or p101 regulatory subunit. Both p110δ and p110γ are expressed predominantly in leukocytes, while the other catalytic subunits are more ubiquitously expressed.

Immunodeficiency disorders have been attributed to both loss- and gain-of-function mutations in the genes encoding p110δ or p85α. There is also now evidence that some of the features caused by p110δ hyperactivation are recapitulated in patients with loss-of-function mutations in the PTEN phosphatase, which functions to dephosphorylate the PIP3 second messenger and suppress PI3K signaling. Very recent data have also emerged indicating pro-inflammatory effects of p110γ inhibition in animals, highlighting a potential negative regulatory function of p110γ predominantly in myeloid cells. Outside the immune system, class I PI3K gene mutations have been found as the cause of a spectrum of rare tissue overgrowth disorders and multi-system syndromes. Integrating knowledge gleaned from these diverse disorders and the wealth of information on fundamental PI3K biology offers the potential to gain a more complete picture of this important pathway and potential effects of its therapeutic manipulation for treatment of a vast array of pathologies.

This Research Topic will provide a comprehensive overview of disorders of PI3K biology and will cover various aspects of the primary immunodeficiency disorder called Activated PI3Kδ Syndrome (APDS), or PASLI disease, caused by mutations in the genes encoding p110δ or p85α. It will also cover the physiological consequences of PTEN deficiency, p110γ inhibition, p85α deficiency, p110δ deficiency, and inherited non-immune overgrowth and metabolic disorders from mutations in PI3K genes.


Keywords: PI3K, Monogenic Disorders, Immunodeficiency, Overgrowth


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

About Frontiers Research Topics

With their unique mixes of varied contributions from Original Research to Review Articles, Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author.

Topic Editors

Loading..

Submission Deadlines

01 December 2017 Manuscript
15 January 2018 Manuscript Extension

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

Loading..

Topic Editors

Loading..

Submission Deadlines

01 December 2017 Manuscript
15 January 2018 Manuscript Extension

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

Loading..
Loading..

total views article views article downloads topic views

}
 
Top countries
Top referring sites
Loading..

Comments

Loading..

Add a comment

Add comment
Back to top