Shc and CEACAM1 interact to regulate the mitogenic action of insulin

Matthew Poy, Randall J. Ruch, Mats A. Fernström, Yoshinori Okabayashi, Sonia M. Najjar

Research output: Contribution to journalArticle

Abstract

CEACAM1, a tumor suppressor (previously known as pp120), is a plasma membrane protein that undergoes phosphorylation on Tyr488 in its cytoplasmic tail by the insulin receptor tyrosine kinase. Co-expression of CEACAM1 with insulin receptors decreased cell growth in response to insulin. Co-immunoprecipitation experiments in intact NIH 3T3 cells and glutathione S-transferase pull-down assays revealed that phosphorylated Tyr488 in CEACAM1 binds to the SH2 domain of Shc, another substrate of the insulin receptor. Overexpressing Shc SH2 domain relieved endogenous Shc from binding to CEACAM1 and restored MAP kinase activity, growth of cells in response to insulin, and their colonization in soft agar. Thus, by binding to Shc, CEACAM1 sequesters this major coupler of Grb2 to the insulin receptor and down-regulates the Ras/MAP kinase mitogenesis pathway. Additionally, CEACAM1 binding to Shc enhances its ability to compete with IRS-1 for phosphorylation by the insulin receptor. This leads to a decrease in IRS-1 binding to phosphoinositide 3′-kinase and to the down-regulation of the phosphoinositide 3′-kinase/Akt pathway that mediates cell proliferation and survival. Thus, binding to Shc appears to constitute a major mechanism for the down-regulatory effect of CEACAM1 on cell proliferation.

Original languageEnglish (US)
Pages (from-to)1076-1084
Number of pages9
JournalJournal of Biological Chemistry
Volume277
Issue number2
DOIs
StatePublished - Jan 11 2002
Externally publishedYes

Fingerprint

Insulin
Insulin Receptor
Phosphotransferases
Phosphorylation
1-Phosphatidylinositol 4-Kinase
src Homology Domains
Cell proliferation
Phosphatidylinositols
Down-Regulation
Cell Proliferation
NIH 3T3 Cells
Cell growth
Cell membranes
Growth
CD66 antigens
Glutathione Transferase
Immunoprecipitation
Agar
Blood Proteins
Tumors

ASJC Scopus subject areas

  • Biochemistry

Cite this

Poy, M., Ruch, R. J., Fernström, M. A., Okabayashi, Y., & Najjar, S. M. (2002). Shc and CEACAM1 interact to regulate the mitogenic action of insulin. Journal of Biological Chemistry, 277(2), 1076-1084. https://doi.org/10.1074/jbc.M108415200

Shc and CEACAM1 interact to regulate the mitogenic action of insulin. / Poy, Matthew; Ruch, Randall J.; Fernström, Mats A.; Okabayashi, Yoshinori; Najjar, Sonia M.

In: Journal of Biological Chemistry, Vol. 277, No. 2, 11.01.2002, p. 1076-1084.

Research output: Contribution to journalArticle

Poy, M, Ruch, RJ, Fernström, MA, Okabayashi, Y & Najjar, SM 2002, 'Shc and CEACAM1 interact to regulate the mitogenic action of insulin', Journal of Biological Chemistry, vol. 277, no. 2, pp. 1076-1084. https://doi.org/10.1074/jbc.M108415200
Poy, Matthew ; Ruch, Randall J. ; Fernström, Mats A. ; Okabayashi, Yoshinori ; Najjar, Sonia M. / Shc and CEACAM1 interact to regulate the mitogenic action of insulin. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 2. pp. 1076-1084.
@article{019c002ba3264397a68a2179bea26fac,
title = "Shc and CEACAM1 interact to regulate the mitogenic action of insulin",
abstract = "CEACAM1, a tumor suppressor (previously known as pp120), is a plasma membrane protein that undergoes phosphorylation on Tyr488 in its cytoplasmic tail by the insulin receptor tyrosine kinase. Co-expression of CEACAM1 with insulin receptors decreased cell growth in response to insulin. Co-immunoprecipitation experiments in intact NIH 3T3 cells and glutathione S-transferase pull-down assays revealed that phosphorylated Tyr488 in CEACAM1 binds to the SH2 domain of Shc, another substrate of the insulin receptor. Overexpressing Shc SH2 domain relieved endogenous Shc from binding to CEACAM1 and restored MAP kinase activity, growth of cells in response to insulin, and their colonization in soft agar. Thus, by binding to Shc, CEACAM1 sequesters this major coupler of Grb2 to the insulin receptor and down-regulates the Ras/MAP kinase mitogenesis pathway. Additionally, CEACAM1 binding to Shc enhances its ability to compete with IRS-1 for phosphorylation by the insulin receptor. This leads to a decrease in IRS-1 binding to phosphoinositide 3′-kinase and to the down-regulation of the phosphoinositide 3′-kinase/Akt pathway that mediates cell proliferation and survival. Thus, binding to Shc appears to constitute a major mechanism for the down-regulatory effect of CEACAM1 on cell proliferation.",
author = "Matthew Poy and Ruch, {Randall J.} and Fernstr{\"o}m, {Mats A.} and Yoshinori Okabayashi and Najjar, {Sonia M.}",
year = "2002",
month = "1",
day = "11",
doi = "10.1074/jbc.M108415200",
language = "English (US)",
volume = "277",
pages = "1076--1084",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "2",

}

TY - JOUR

T1 - Shc and CEACAM1 interact to regulate the mitogenic action of insulin

AU - Poy, Matthew

AU - Ruch, Randall J.

AU - Fernström, Mats A.

AU - Okabayashi, Yoshinori

AU - Najjar, Sonia M.

PY - 2002/1/11

Y1 - 2002/1/11

N2 - CEACAM1, a tumor suppressor (previously known as pp120), is a plasma membrane protein that undergoes phosphorylation on Tyr488 in its cytoplasmic tail by the insulin receptor tyrosine kinase. Co-expression of CEACAM1 with insulin receptors decreased cell growth in response to insulin. Co-immunoprecipitation experiments in intact NIH 3T3 cells and glutathione S-transferase pull-down assays revealed that phosphorylated Tyr488 in CEACAM1 binds to the SH2 domain of Shc, another substrate of the insulin receptor. Overexpressing Shc SH2 domain relieved endogenous Shc from binding to CEACAM1 and restored MAP kinase activity, growth of cells in response to insulin, and their colonization in soft agar. Thus, by binding to Shc, CEACAM1 sequesters this major coupler of Grb2 to the insulin receptor and down-regulates the Ras/MAP kinase mitogenesis pathway. Additionally, CEACAM1 binding to Shc enhances its ability to compete with IRS-1 for phosphorylation by the insulin receptor. This leads to a decrease in IRS-1 binding to phosphoinositide 3′-kinase and to the down-regulation of the phosphoinositide 3′-kinase/Akt pathway that mediates cell proliferation and survival. Thus, binding to Shc appears to constitute a major mechanism for the down-regulatory effect of CEACAM1 on cell proliferation.

AB - CEACAM1, a tumor suppressor (previously known as pp120), is a plasma membrane protein that undergoes phosphorylation on Tyr488 in its cytoplasmic tail by the insulin receptor tyrosine kinase. Co-expression of CEACAM1 with insulin receptors decreased cell growth in response to insulin. Co-immunoprecipitation experiments in intact NIH 3T3 cells and glutathione S-transferase pull-down assays revealed that phosphorylated Tyr488 in CEACAM1 binds to the SH2 domain of Shc, another substrate of the insulin receptor. Overexpressing Shc SH2 domain relieved endogenous Shc from binding to CEACAM1 and restored MAP kinase activity, growth of cells in response to insulin, and their colonization in soft agar. Thus, by binding to Shc, CEACAM1 sequesters this major coupler of Grb2 to the insulin receptor and down-regulates the Ras/MAP kinase mitogenesis pathway. Additionally, CEACAM1 binding to Shc enhances its ability to compete with IRS-1 for phosphorylation by the insulin receptor. This leads to a decrease in IRS-1 binding to phosphoinositide 3′-kinase and to the down-regulation of the phosphoinositide 3′-kinase/Akt pathway that mediates cell proliferation and survival. Thus, binding to Shc appears to constitute a major mechanism for the down-regulatory effect of CEACAM1 on cell proliferation.

UR - http://www.scopus.com/inward/record.url?scp=0037059799&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037059799&partnerID=8YFLogxK

U2 - 10.1074/jbc.M108415200

DO - 10.1074/jbc.M108415200

M3 - Article

C2 - 11694516

AN - SCOPUS:0037059799

VL - 277

SP - 1076

EP - 1084

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 2

ER -