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

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Role of TAPP1 and TAPP2 adaptor binding to PtdIns(3,4) P2 in regulating insulin sensitivity defined by knock-in analysis. / Wullschleger, Stephan; Wasserman, David H.; Gray, Alex; Sakamoto, Kei; Alessi, Dario R.

In: Biochemical Journal, Vol. 434, No. 2, 01.03.2011, p. 265-274.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Wullschleger, S, Wasserman, DH, Gray, A, Sakamoto, K & Alessi, DR 2011, 'Role of TAPP1 and TAPP2 adaptor binding to PtdIns(3,4) P2 in regulating insulin sensitivity defined by knock-in analysis', Biochemical Journal, vol. 434, no. 2, pp. 265-274. https://doi.org/10.1042/BJ20102012

APA

Wullschleger, S., Wasserman, D. H., Gray, A., Sakamoto, K., & Alessi, D. R. (2011). Role of TAPP1 and TAPP2 adaptor binding to PtdIns(3,4) P2 in regulating insulin sensitivity defined by knock-in analysis. Biochemical Journal, 434(2), 265-274. https://doi.org/10.1042/BJ20102012

Vancouver

Wullschleger S, Wasserman DH, Gray A, Sakamoto K, Alessi DR. Role of TAPP1 and TAPP2 adaptor binding to PtdIns(3,4) P2 in regulating insulin sensitivity defined by knock-in analysis. Biochemical Journal. 2011 Mar 1;434(2):265-274. https://doi.org/10.1042/BJ20102012

Author

Wullschleger, Stephan ; Wasserman, David H. ; Gray, Alex ; Sakamoto, Kei ; Alessi, Dario R. / Role of TAPP1 and TAPP2 adaptor binding to PtdIns(3,4) P2 in regulating insulin sensitivity defined by knock-in analysis. In: Biochemical Journal. 2011 ; Vol. 434, No. 2. pp. 265-274.

Bibtex

@article{2cbcffc48cd9493daa54889e6d60925b,
title = "Role of TAPP1 and TAPP2 adaptor binding to PtdIns(3,4) P2 in regulating insulin sensitivity defined by knock-in analysis",
abstract = "Insulin sensitivity is critically dependent on the activity of PI3K (phosphoinositide 3-kinase) and generation of the PtdIns(3,4,5)P3 second messenger. PtdIns(3,4,5)P3 can be broken down to PtdIns(3,4)P2 through the action of the SHIPs (Src-homology-2-domain- containing inositol phosphatases). As PtdIns(3,4)P2 levels peak after those of PtdIns(3,4,5)P3, it has been proposed that PtdIns(3,4)P2 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)P2 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)P2. These homozygous TAPP1R211L/R211LTAPP2 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/R211LTAPP2R218L/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 adaptors to PtdIns(3,4)P2 function as negative regulators of the insulin and PI3K signalling pathways.",
keywords = "Insulin signalling, Phosphoinositide 3-kinase (PI3K), Pleckstrin homology domain (PH domain), Protein tyrosine phosphatase, Tandem pleckstrin homology-domain-containing protein (TAPP)",
author = "Stephan Wullschleger and Wasserman, {David H.} and Alex Gray and Kei Sakamoto and Alessi, {Dario R.}",
year = "2011",
month = mar,
day = "1",
doi = "10.1042/BJ20102012",
language = "English",
volume = "434",
pages = "265--274",
journal = "Biochemical Journal",
issn = "0264-6021",
publisher = "Portland Press Ltd.",
number = "2",

}

RIS

TY - JOUR

T1 - Role of TAPP1 and TAPP2 adaptor binding to PtdIns(3,4) P2 in regulating insulin sensitivity defined by knock-in analysis

AU - Wullschleger, Stephan

AU - Wasserman, David H.

AU - Gray, Alex

AU - Sakamoto, Kei

AU - Alessi, Dario R.

PY - 2011/3/1

Y1 - 2011/3/1

N2 - Insulin sensitivity is critically dependent on the activity of PI3K (phosphoinositide 3-kinase) and generation of the PtdIns(3,4,5)P3 second messenger. PtdIns(3,4,5)P3 can be broken down to PtdIns(3,4)P2 through the action of the SHIPs (Src-homology-2-domain- containing inositol phosphatases). As PtdIns(3,4)P2 levels peak after those of PtdIns(3,4,5)P3, it has been proposed that PtdIns(3,4)P2 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)P2 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)P2. These homozygous TAPP1R211L/R211LTAPP2 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/R211LTAPP2R218L/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 adaptors to PtdIns(3,4)P2 function as negative regulators of the insulin and PI3K signalling pathways.

AB - Insulin sensitivity is critically dependent on the activity of PI3K (phosphoinositide 3-kinase) and generation of the PtdIns(3,4,5)P3 second messenger. PtdIns(3,4,5)P3 can be broken down to PtdIns(3,4)P2 through the action of the SHIPs (Src-homology-2-domain- containing inositol phosphatases). As PtdIns(3,4)P2 levels peak after those of PtdIns(3,4,5)P3, it has been proposed that PtdIns(3,4)P2 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)P2 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)P2. These homozygous TAPP1R211L/R211LTAPP2 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/R211LTAPP2R218L/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 adaptors to PtdIns(3,4)P2 function as negative regulators of the insulin and PI3K signalling pathways.

KW - Insulin signalling

KW - Phosphoinositide 3-kinase (PI3K)

KW - Pleckstrin homology domain (PH domain)

KW - Protein tyrosine phosphatase

KW - Tandem pleckstrin homology-domain-containing protein (TAPP)

UR - http://www.scopus.com/inward/record.url?scp=79951539991&partnerID=8YFLogxK

U2 - 10.1042/BJ20102012

DO - 10.1042/BJ20102012

M3 - Journal article

C2 - 21204784

AN - SCOPUS:79951539991

VL - 434

SP - 265

EP - 274

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 2

ER -

ID: 239572424