Lipid and Protein Co-Regulation of PI3K Effectors Akt and Itk in Lymphocytes.

Xinxin Wang,Yina Hsing Huang,Leonard Benjamin Hills

doi:10.3389/fimmu.2015.00117

Xinxin Wang, Yina Hsing Huang + Show 1 more

Open Access

https://doi.org/10.3389/fimmu.2015.00117

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Abstract

The phosphoinositide 3-kinase (PI 3-kinase, PI3K) pathway transduces signals critical for lymphocyte function. PI3K generates the phospholipid PIP3 at the plasma membrane to recruit proteins that contain pleckstrin homology (PH) domains – a conserved domain found in hundreds of mammalian proteins. PH domain–PIP3 interactions allow for rapid signal propagation and confer a spatial component to these signals. The kinases Akt and Itk are key PI3K effectors that bind PIP3 via their PH domains and mediate vital processes – such as survival, activation, and differentiation – in lymphocytes. Here, we review the roles and regulation of PI3K signaling in lymphocytes with a specific emphasis on Akt and Itk. We also discuss these and other PH domain-containing proteins as they relate more broadly to immune cell function. Finally, we highlight the emerging view of PH domains as multifunctional protein domains that often bind both lipid and protein substrates to exert their effects.

Highlights

Phosphoinositide 3-kinase (PI3K) activation is important for lymphocyte survival, activation, differentiation, and migration
Proteins regulated in this manner, such as the PI3K effector kinases Akt and Itk, are indispensable for immune cell function
Mutations that disrupt the lipid-binding capacity of pleckstrin homology (PH) domains are known to result in human disease, a phenomenon perhaps best demonstrated by the immunologic defects associated with mutations in Tec family kinases

Summary

Introduction

Phosphoinositide 3-kinase (PI3K) activation is important for lymphocyte survival, activation, differentiation, and migration. High affinity and specificity binding between PIP3 and pleckstrin homology (PH) domains of PI3K effectors helps to recruit and activate these effectors at the plasma membrane (Figure 2). Akt and Itk in lymphocytes domain-containing proteins are activated at the plasma membrane and mediate important cellular responses such as cytoskeleton rearrangement, cell growth, proliferation, and survival.

Results

Conclusion