Integrin-associated protein association with SRC homology 2 domain containing tyrosine phosphatase substrate 1 regulates igf-I signaling in vivo.
OBJECTIVE
Smooth muscle cell (SMC) maintained in medium containing normal levels of glucose do not proliferate in response to IGF-I, whereas cells maintained in medium containing 25 mmol/l glucose can respond. The aim of this study was to determine whether signaling events that have been shown to be required for stimulation of SMC growth were regulated by glucose concentrations in vivo.


METHODS
We compared IGF-I-stimulated signaling events and growth in the aortic smooth muscle cells from normal and hyperglycemic mice.


RESULTS
We determined that, in mice, hyperglycemia was associated with an increase in formation of the integrin-associated protein (IAP)/Src homology 2 domaine containing tyrosine phosphatase substrate 1 (SHPS-1) complex. There was a corresponding increase in Shc recruitment to SHPS-1 and Shc phosphorylation in response to IGF-I. There was also an increase in mitogen-activated protein kinase activation and SMC proliferation. The increase in IAP association with SHPS-1 in hyperglycemia appeared to be due to the protection of IAP from cleavage that occurred during exposure to normal glucose. In addition, we demonstrated that the protease responsible for IAP cleavage was matrix metalloprotease-2. An anti-IAP antibody that disrupted the IAP-SHPS-1 association resulted in complete inhibition of IGF-I-stimulated proliferation.


CONCLUSIONS
Taken together, our results support a model in which hyperglycemia is associated with a reduction in IAP cleavage, thus allowing the formation of the IAP-SHPS-1 signaling complex that is required for IGF-I-stimulated proliferation of SMC.
Maile
Laura A
LA
Division of Endocrinology, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA. laura_maile@med.unc.edu
Capps
Byron E
BE
Miller
Emily C
EC
Aday
Ariel W
AW
Clemmons
David R
DR
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D051928:CD47 Antigen / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000473:pathology; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism; D015398:Signal Transduction; D018909:src Homology Domains
D001786:Blood Glucose; D051928:CD47 Antigen; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; D055765:Shc Signaling Adaptor Proteins; D007334:Insulin-Like Growth Factor I; D002784:Cholesterol; D005947:Glucose