Role of TAPP1 and TAPP2 adaptor binding to PtdIns(3,4)P2 in regulating insulin sensitivity defined by knock-in analysis.

Wullschleger S, Wasserman DH, Gray A, Sakamoto K, Alessi DR
Biochem J. 2011 434 (2): 265-74

PMID: 21204784 · PMCID: PMC4461655 · DOI:10.1042/BJ20102012

Insulin sensitivity is critically dependent on the activity of PI3K (phosphoinositide 3-kinase) and generation of the PtdIns(3,4,5)P(3) second messenger. PtdIns(3,4,5)P(3) can be broken down to PtdIns(3,4)P(2) through the action of the SHIPs (Src-homology-2-domain-containing inositol phosphatases). As PtdIns(3,4)P(2) levels peak after those of PtdIns(3,4,5)P(3), it has been proposed that PtdIns(3,4)P(2) controls a negative-feedback loop that down-regulates the insulin and PI3K network. Previously, we identified two related adaptor proteins termed TAPP [tandem PH (pleckstrin homology)-domain-containing protein] 1 and TAPP2 that specifically bind to PtdIns(3,4)P(2) through their C-terminal PH domain. To determine whether TAPP1 and TAPP2 play a role in regulating insulin sensitivity, we generated knock-in mice that express normal endogenous levels of mutant TAPP1 and TAPP2 that are incapable of binding PtdIns(3,4)P(2). These homozygous TAPP1(R211L/R211L) TAPP2(R218L/R218L) double knock-in mice are viable and exhibit significantly enhanced activation of Akt, a key downstream mediator of insulin signalling. Consistent with increased PI3K and Akt activity, the double knock-in mice display enhanced whole body insulin sensitivity and disposal of glucose uptake into muscle tissues. We also generated wild-type and double TAPP1(R211L/R211L) TAPP2(R218L/R218L) knock-in embryonic fibroblasts and found that insulin triggered enhanced production of PtdIns(3,4,5)P(3) and Akt activity in the double knock-in fibroblasts. These observations provide the first genetic evidence to support the notion that binding of TAPP1 and TAPP2 adap-tors to PtdIns(3,4)P(2) function as negative regulators of the insulin and PI3K signalling pathways.

© The Authors Journal compilation © 2011 Biochemical Society

MeSH Terms (15)

Animals Binding Sites Embryo, Mammalian Female Gene Knock-In Techniques Insulin Intracellular Signaling Peptides and Proteins Male Membrane Proteins Mice Mice, Inbred C57BL Phosphatidylinositol 3-Kinases Phosphatidylinositol Phosphates Proto-Oncogene Proteins c-akt Signal Transduction

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