Two new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5

Dongsheng Cai, Sirano Dhe-Paganon, Peter A. Melendez, Jongsoon Lee, Steven E. Shoelson

Research output: Contribution to journalArticle

132 Citations (Scopus)

Abstract

We have identified two new human genes that encode proteins with tandem pleckstrin homology-phosphotyrosine binding (PH-PTB) domains at their amino termini. Because the other known PH-PTB proteins (insulin receptor substrates: IRS-1, IRS-2, IRS-3, and IRS-4, and the downstream of kinases: DOK-1, DOK-2, and DOK-3) are substrates of insulin and insulin-like growth factor (IGF)-1 receptors, we asked whether these new proteins, termed IRS5/DOK4 and IRS6/DOK5, might also have roles in insulin and IGF-1 signaling. Northern analyses indicate that IRS5/DOK4 is ubiquitously expressed but most abundant in kidney and liver. IRS6/DOK5 expression is highest in skeletal muscle. Both proteins are tyrosine-phosphorylated in response to insulin and IGF-1 in transfected cells, although the kinetics differ. Insulin receptor-phosphorylated IRS5/DOK4 associates with RasGAP, Crk, Src, and Fyn, but not phosphatidylinositol 3-kinase p85, Grb2, SHP-2, Nck, or phospholipase Cγ Src homology 2 domains, and activates MAPK in cells. IRS6/DOK5 neither associates with these Src homology 2 domains nor activates MAPK. IRS5/DOK4 and IRS6/DOK5 represent two new signaling proteins with potential roles in insulin and IGF-1 action.

Original languageEnglish (US)
Pages (from-to)25323-25330
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number28
DOIs
StatePublished - Jul 11 2003
Externally publishedYes

Fingerprint

Somatomedins
Insulin
Phosphotyrosine
src Homology Domains
Insulin Receptor
Substrates
Proteins
Phosphatidylinositol 3-Kinase
Somatomedin Receptors
Insulin Receptor Substrate Proteins
Type C Phospholipases
Liver
Tyrosine
Muscle
Carrier Proteins
Skeletal Muscle
Phosphotransferases
Genes
Kidney
Kinetics

ASJC Scopus subject areas

  • Biochemistry

Cite this

Cai, D., Dhe-Paganon, S., Melendez, P. A., Lee, J., & Shoelson, S. E. (2003). Two new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5. Journal of Biological Chemistry, 278(28), 25323-25330. https://doi.org/10.1074/jbc.M212430200

Two new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5. / Cai, Dongsheng; Dhe-Paganon, Sirano; Melendez, Peter A.; Lee, Jongsoon; Shoelson, Steven E.

In: Journal of Biological Chemistry, Vol. 278, No. 28, 11.07.2003, p. 25323-25330.

Research output: Contribution to journalArticle

Cai, D, Dhe-Paganon, S, Melendez, PA, Lee, J & Shoelson, SE 2003, 'Two new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5', Journal of Biological Chemistry, vol. 278, no. 28, pp. 25323-25330. https://doi.org/10.1074/jbc.M212430200
Cai, Dongsheng ; Dhe-Paganon, Sirano ; Melendez, Peter A. ; Lee, Jongsoon ; Shoelson, Steven E. / Two new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 28. pp. 25323-25330.
@article{581f946eaccf4d80bccec044d85e5599,
title = "Two new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5",
abstract = "We have identified two new human genes that encode proteins with tandem pleckstrin homology-phosphotyrosine binding (PH-PTB) domains at their amino termini. Because the other known PH-PTB proteins (insulin receptor substrates: IRS-1, IRS-2, IRS-3, and IRS-4, and the downstream of kinases: DOK-1, DOK-2, and DOK-3) are substrates of insulin and insulin-like growth factor (IGF)-1 receptors, we asked whether these new proteins, termed IRS5/DOK4 and IRS6/DOK5, might also have roles in insulin and IGF-1 signaling. Northern analyses indicate that IRS5/DOK4 is ubiquitously expressed but most abundant in kidney and liver. IRS6/DOK5 expression is highest in skeletal muscle. Both proteins are tyrosine-phosphorylated in response to insulin and IGF-1 in transfected cells, although the kinetics differ. Insulin receptor-phosphorylated IRS5/DOK4 associates with RasGAP, Crk, Src, and Fyn, but not phosphatidylinositol 3-kinase p85, Grb2, SHP-2, Nck, or phospholipase Cγ Src homology 2 domains, and activates MAPK in cells. IRS6/DOK5 neither associates with these Src homology 2 domains nor activates MAPK. IRS5/DOK4 and IRS6/DOK5 represent two new signaling proteins with potential roles in insulin and IGF-1 action.",
author = "Dongsheng Cai and Sirano Dhe-Paganon and Melendez, {Peter A.} and Jongsoon Lee and Shoelson, {Steven E.}",
year = "2003",
month = "7",
day = "11",
doi = "10.1074/jbc.M212430200",
language = "English (US)",
volume = "278",
pages = "25323--25330",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "28",

}

TY - JOUR

T1 - Two new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5

AU - Cai, Dongsheng

AU - Dhe-Paganon, Sirano

AU - Melendez, Peter A.

AU - Lee, Jongsoon

AU - Shoelson, Steven E.

PY - 2003/7/11

Y1 - 2003/7/11

N2 - We have identified two new human genes that encode proteins with tandem pleckstrin homology-phosphotyrosine binding (PH-PTB) domains at their amino termini. Because the other known PH-PTB proteins (insulin receptor substrates: IRS-1, IRS-2, IRS-3, and IRS-4, and the downstream of kinases: DOK-1, DOK-2, and DOK-3) are substrates of insulin and insulin-like growth factor (IGF)-1 receptors, we asked whether these new proteins, termed IRS5/DOK4 and IRS6/DOK5, might also have roles in insulin and IGF-1 signaling. Northern analyses indicate that IRS5/DOK4 is ubiquitously expressed but most abundant in kidney and liver. IRS6/DOK5 expression is highest in skeletal muscle. Both proteins are tyrosine-phosphorylated in response to insulin and IGF-1 in transfected cells, although the kinetics differ. Insulin receptor-phosphorylated IRS5/DOK4 associates with RasGAP, Crk, Src, and Fyn, but not phosphatidylinositol 3-kinase p85, Grb2, SHP-2, Nck, or phospholipase Cγ Src homology 2 domains, and activates MAPK in cells. IRS6/DOK5 neither associates with these Src homology 2 domains nor activates MAPK. IRS5/DOK4 and IRS6/DOK5 represent two new signaling proteins with potential roles in insulin and IGF-1 action.

AB - We have identified two new human genes that encode proteins with tandem pleckstrin homology-phosphotyrosine binding (PH-PTB) domains at their amino termini. Because the other known PH-PTB proteins (insulin receptor substrates: IRS-1, IRS-2, IRS-3, and IRS-4, and the downstream of kinases: DOK-1, DOK-2, and DOK-3) are substrates of insulin and insulin-like growth factor (IGF)-1 receptors, we asked whether these new proteins, termed IRS5/DOK4 and IRS6/DOK5, might also have roles in insulin and IGF-1 signaling. Northern analyses indicate that IRS5/DOK4 is ubiquitously expressed but most abundant in kidney and liver. IRS6/DOK5 expression is highest in skeletal muscle. Both proteins are tyrosine-phosphorylated in response to insulin and IGF-1 in transfected cells, although the kinetics differ. Insulin receptor-phosphorylated IRS5/DOK4 associates with RasGAP, Crk, Src, and Fyn, but not phosphatidylinositol 3-kinase p85, Grb2, SHP-2, Nck, or phospholipase Cγ Src homology 2 domains, and activates MAPK in cells. IRS6/DOK5 neither associates with these Src homology 2 domains nor activates MAPK. IRS5/DOK4 and IRS6/DOK5 represent two new signaling proteins with potential roles in insulin and IGF-1 action.

UR - http://www.scopus.com/inward/record.url?scp=0037816152&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037816152&partnerID=8YFLogxK

U2 - 10.1074/jbc.M212430200

DO - 10.1074/jbc.M212430200

M3 - Article

C2 - 12730241

AN - SCOPUS:0037816152

VL - 278

SP - 25323

EP - 25330

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 28

ER -