The
insulin and
insulin-like growth factor-1 (IGF-1) receptors mediate signaling for energy uptake and growth through
insulin receptor substrates (IRSs), which interact with these receptors as well as with downstream effectors.
Oxygen is essential not only for
ATP production through oxidative phosphorylation but also for many cellular processes, particularly those involved in energy homeostasis. The
oxygen tension in vivo is significantly lower than that in the air and can vary widely depending on the tissue as well as on perfusion and oxygen consumption. How
oxygen tension affects IRSs and their functions is poorly understood. Our findings indicate that transient
hypoxia (1%
oxygen) leads to
caspase-mediated cleavage of IRS-1 without inducing cell death. The IRS-1
protein level rebounds rapidly upon return to normoxia.
Protein tyrosine phosphatases (
PTPs) appear to be important for the IRS-1 cleavage because
tyrosine phosphorylation of the
insulin receptor was decreased in
hypoxia and IRS-1 cleavage could be blocked either with H(2)O(2) or with
vanadate, each of which inhibits
PTPs. Activity of Akt, a downstream effector of
insulin and
IGF-1 signaling that is known to suppress
caspase activation, was suppressed in
hypoxia. Overexpression of dominant-negative Akt led to IRS-1 cleavage even in normoxia, and overexpression of constitutively active Akt partially suppressed IRS-1 cleavage in
hypoxia, suggesting that
hypoxia-mediated suppression of Akt may induce
caspase-mediated IRS-1 cleavage. In conclusion, our study elucidates a mechanism by which
insulin and
IGF-1 signaling can be matched to the
oxygen level that is available to support growth and energy metabolism.