PubMed Journals: J Biol Chem
Source: PMID: 11606564
⇦ ⇨ J Biol Chem. 2002 Jan 11;277(2):1531-7.
⇩ Epub 2001 Oct 17.
Phosphorylation of Ser307 in
insulin receptor substrate-1 blocks interactions
with the insulin receptor and inhibits insulin
Aguirre V(1), Werner ED, Giraud J, Lee YH,
Shoelson SE, White MF.
(1) Howard Hughes Medical Institute,
Joslin Diabetes Center, Harvard Medical School,
Boston, Massachusetts 02215, USA.
Serine phosphorylation of
insulin receptor substrate-1 (IRS-1) inhibits
insulin signal transduction in a variety
of cell backgrounds, which might contribute
to peripheral insulin resistance. However,
because of the large number of potential
phosphorylation sites, the mechanism of
inhibition has been difficult to determine. One
serine residue located near the
phosphotyrosine-binding (PTB) domain in
IRS-1 (Ser(307) in rat IRS-1 or Ser(312)
in human IRS-1) is phosphorylated via several
mechanisms, including insulin-stimulated
kinases or stress-activated kinases like
JNK1. During a yeast tri-hybrid assay,
phosphorylation of Ser(307) by JNK1 disrupted
the interaction between the catalytic domain
of the insulin receptor and the PTB domain
of IRS-1. In 32D myeloid progenitor cells,
phosphorylation of Ser(307) inhibited insulin
stimulation of the phosphatidylinositol
3-kinase and MAPK cascades. These results
suggest that inhibition of PTB domain function
in IRS-1 by phosphorylation of Ser(307)
(Ser(312) in human IRS-1) might be a general
mechanism to regulate insulin signaling.
DOI: 10.1074/jbc.M101521200 PMID: 11606564
[Indexed for MEDLINE]