Wednesday, November 28, 2018 - 13:00 to 14:00
CTIR Sir Kenneth and Lady Noreen Murray Seminar Room
Professor Doreen Cantrell CBE FRS FRSE FMedSci
Professor Aaron Marshall
Department of Immunology University of Manitoba
Dundee Cell Signalling Lecture
Tayside Immunology Group and the Division of Cell Signalling and Immunology
Class I phosphoinositide 3-kinases (PI3Ks) play critical roles in B lymphocyte activation by phosphorylating plasma membrane lipids to generate two distinct phosphoinositide products, PI(3,4,5)P3 and PI(3,4)P2. During B cell activation, PI3K generates the phosphoinositide PI(3,4,5)P3 which can be rapidly converted to PI(3,4)P2 by the critical inositol phosphatase SHIP. The inositol polyphosphate 4-phosphatase (INPP4) further regulates the PI3K pathway by hydrolysis of PI(3,4)P2 to produce PI(3)P1. Distinct signaling molecules bind to PIP3, including the protein kinase Btk, to PI(3,4)P2, such as adaptors TAPP1, TAPP2 and lammelipodin (Lpd) or to both of these PIs, such as the kinase Akt or adaptor Bam32/DAPP1. Our work is focused primarily on the regulation and functions of PI(3,4)P2 and its binding proteins in B lymphocytes. We and others have found that B cell survival, cytoskeletal reorganization, migration and metabolic activity can be influenced by class I PI3Ks; however the respective contributions of distinct PIs and their binding proteins remain as important subjects of investigation. We have implicated PI(3,4)P2 and its binding proteins TAPP1, TAPP2, Bam32 and lamellipodin in control of B cell adhesion, migration and antigen receptor signaling. Uncoupling of TAPP adaptors from PI(3,4)P2 in vivo leads to B cell dysregulation, metabolic abnormalities and autoimmunity. Together our studies strongly implicate PI(3,4)P2 as a functionally-significant and independently-regulated second messenger downstream of class I PI 3-kinases. Current work is investigating the roles of INPP4A and INPP4B in B cell biology as well as the functional impact of clinically-relevant PI3Kdelta and PI3Kgamma inhibitors on B cell biology.