Role for the juxtamembrane domain of the insulin receptor in mediating the effect of PP120 on insulin endocytosis

S. M. Najjar, S. Li Calzi, Curtis Choice

Research output: Contribution to journalArticle

Abstract

pp120, a plasma membrane h, is a sutbstrate of the insulin receptor tyrosine kinase in the liver. Co-expression of pp120 and insulin receptors A, but not B, in NIH 3T3 fibroblasts increased receptor-mediated insulin endocytosis and degradation by 2- to 3-fold as compared to cells expressing insulin receptors alone. In contrast, co-expression of ppl20 and the IGF-1 receptor did not increase receptor-mediated IGF-1 internalization in transfected NIH 3T3 cells. Substitution of the C-terminus domain of the 3-subunit of the IGF-1 receptor with the corresponding domain of lice insulin receptor restored ppl20 phosphorylation, but failed to promote ppl20 effect on IGF-1 internalization. To further identify receptor domains required to mediate ppl20 effect on insulin endocytosis, we examined pp120 effect on insulin endocytosis via a mutant insulin receptor in which Tyr960 in the juxtamembrane domain was mutated to Phe. Unlike most other susbtrates, ppl20 was normally phosphorylated by this mutant receptor. Interestingly, insulin endocytosis and degradation were reduced 1.5- to 2-fold when ppl20 was co-expressed with this mutant. This confirms that pp120 phosphorylation per se is not sufficient to mediate ppl20 effect on insulin internalization. Thus. additional molecules, such as IRS-1, IRS-2 and She, that require intact phosphorylation of the receptor juxtamembrane domain may regulate insulin endocytosis by a ppl20-mediated mechanism.

Original languageEnglish (US)
JournalFASEB Journal
Volume11
Issue number9
StatePublished - 1997
Externally publishedYes

Fingerprint

Insulin Receptor
endocytosis
Endocytosis
insulin
IGF Type 1 Receptor
Insulin
Phosphorylation
receptors
phosphorylation
Insulin-Like Growth Factor I
mutants
Phthiraptera
NIH 3T3 Cells
Degradation
degradation
lice
Fibroblasts
Cell membranes
Liver
fibroblasts

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Role for the juxtamembrane domain of the insulin receptor in mediating the effect of PP120 on insulin endocytosis. / Najjar, S. M.; Li Calzi, S.; Choice, Curtis.

In: FASEB Journal, Vol. 11, No. 9, 1997.

Research output: Contribution to journalArticle

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AB - pp120, a plasma membrane h, is a sutbstrate of the insulin receptor tyrosine kinase in the liver. Co-expression of pp120 and insulin receptors A, but not B, in NIH 3T3 fibroblasts increased receptor-mediated insulin endocytosis and degradation by 2- to 3-fold as compared to cells expressing insulin receptors alone. In contrast, co-expression of ppl20 and the IGF-1 receptor did not increase receptor-mediated IGF-1 internalization in transfected NIH 3T3 cells. Substitution of the C-terminus domain of the 3-subunit of the IGF-1 receptor with the corresponding domain of lice insulin receptor restored ppl20 phosphorylation, but failed to promote ppl20 effect on IGF-1 internalization. To further identify receptor domains required to mediate ppl20 effect on insulin endocytosis, we examined pp120 effect on insulin endocytosis via a mutant insulin receptor in which Tyr960 in the juxtamembrane domain was mutated to Phe. Unlike most other susbtrates, ppl20 was normally phosphorylated by this mutant receptor. Interestingly, insulin endocytosis and degradation were reduced 1.5- to 2-fold when ppl20 was co-expressed with this mutant. This confirms that pp120 phosphorylation per se is not sufficient to mediate ppl20 effect on insulin internalization. Thus. additional molecules, such as IRS-1, IRS-2 and She, that require intact phosphorylation of the receptor juxtamembrane domain may regulate insulin endocytosis by a ppl20-mediated mechanism.

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