Contrasting Signaling Pathways of α1A- and α1B-Adrenergic Receptor Subtype Activation of Phosphatidylinositol 3-Kinase and Ras in Transfected NIH3T3 Cells

Abstract IGF-I is an endocrine and paracrine regulator of skeletal homeostasis, principally by virtue of its anabolic effects on osteoblastic cells. In the current study, we examined the intracellular signaling pathways by which IGF-I promotes proliferation and survival in SaOS-2 human osteoblastic cells. Inhibition of each of the phosphatidylinositol-3 kinase (PI-3 kinase), p42/44 MAPK, and p70s6 kinase pathways partially inhibited the ability of IGF-I to stimulate osteoblast proliferation and survival. Because activation of p70s6 kinase is downstream of both PI-3 kinase and p42/44 MAPK activation in osteoblasts treated with IGF-I, this ribosomal kinase represents a convergence point for IGF-I-induced PI-3 kinase and p42/44 MAPK signaling in osteoblastic cells. In addition, abrogation of PI-3 kinase-dependent Akt signaling, which does not inhibit IGF-I-induced p70s6 kinase phosphorylation, also inhibited the antiapoptotic effects of IGF-I in osteoblasts. Finally, interruption of Gβγ signaling partially abrogated the ability of IGF-I to promote osteoblast survival, without inhibiting signaling through PI-3 kinase/Akt, p42/44 MAPKs, or p70s6 kinase. These data suggest that IGF-I signals osteoblast mitogenesis and survival through parallel, partly overlapping intracellular pathways involving PI-3 kinase, p42/44 MAPKs, and Gβγ subunits.

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The Phosphatidylinositol 3-Kinase-Akt Pathway Limits Lipopolysaccharide Activation of Signaling Pathways and Expression of Inflammatory Mediators in Human Monocytic Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m203298200 ◽

2002 ◽

Vol 277 (35) ◽

pp. 32124-32132 ◽

Cited By ~ 540

Author(s):

Mausumee Guha ◽

Nigel Mackman

Keyword(s):

Signaling Pathways ◽

Inflammatory Mediators ◽

Akt Pathway ◽

Phosphatidylinositol 3 Kinase ◽

Monocytic Cells ◽

Phosphatidylinositol 3

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Differentiated Phenotype of Smooth Muscle Cells Depends on Signaling Pathways through Insulin-like Growth Factors and Phosphatidylinositol 3-Kinase

Journal of Biological Chemistry ◽

10.1074/jbc.273.44.28860 ◽

1998 ◽

Vol 273 (44) ◽

pp. 28860-28867 ◽

Cited By ~ 123

Author(s):

Ken’ichiro Hayashi ◽

Hiroshi Saga ◽

Yoshihiro Chimori ◽

Kazuhiro Kimura ◽

Yuka Yamanaka ◽

...

Keyword(s):

Smooth Muscle ◽

Growth Factors ◽

Smooth Muscle Cells ◽

Signaling Pathways ◽

Muscle Cells ◽

Phosphatidylinositol 3 Kinase ◽

Insulin Like Growth Factors ◽

Phosphatidylinositol 3

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Insulin can block apoptosis by decreasing oxidative stress via phosphatidylinositol 3-kinase- and extracellular signal-regulated protein kinase-dependent signaling pathways in HepG2 cells

Acta Endocrinologica ◽

10.1530/eje.0.1480147 ◽

2003 ◽

pp. 147-155 ◽

Cited By ~ 52

Author(s):

S Kang ◽

J Song ◽

H Kang ◽

S Kim ◽

Y Lee ◽

...

Keyword(s):

Oxidative Stress ◽

Protein Kinase ◽

Signaling Pathways ◽

Hepg2 Cells ◽

Caspase 3 ◽

Pi3 Kinase ◽

Phosphatidylinositol 3 Kinase ◽

Extracellular Signal ◽

Apoptotic Activity ◽

Phosphatidylinositol 3

OBJECTIVE: Insulin has well-known activities in controlling energy metabolism, cellular proliferation and biosynthesis of functional molecules to maintain a biological homeostasis. Recently, several studies have suggested that insulin may protect cells from apoptosis in different cell lines; however, little is known about the nature of its anti-apoptotic activity. In many clinical disorders, including type 2 diabetes mellitus, oxidative stress and the production of reactive oxygen species (ROS) is increased. With these facts as a background, we examined here whether insulin protects HepG2 cells from apoptosis by decreasing oxidative stress and, if so, which signaling steps are involved in this process. METHODS: Intracellular DNA content, the degree of nuclear condensation or poly(ADP-ribose) polymerase hydrolysis was measured to verify the occurrence of apoptotic events. Caspase-3 activity and ROS accumulation within cells were also measured. Western blot analysis was performed to identify signaling molecules activated in response to insulin. RESULTS: Serum starvation resulted in a marked accumulation of ROS, activation of caspase-3, and subsequent apoptotic cell death which were, in turn, markedly blocked by the addition of insulin. The anti-apoptotic activity of insulin was sensitive to blockade of two different signaling steps, activations of phosphatidylinositol 3-kinase (PI3 kinase) and extracellular signal-regulated protein kinase (ERK). CONCLUSION: Insulin exerts an anti-apoptotic activity by suppressing the excessive accumulation of ROS within cells through signaling pathways including stimulation of PI3 kinase and ERK in HepG2 cells.

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