Insulin-like growth factor-1 (IGF-1) induces the activation/phosphorylation of Akt kinase and cAMP response element-binding protein (CREB) by activating different signaling pathways in PC12 cells

Wen-Hua Zheng,Rémi Quirion

doi:10.1186/1471-2202-7-51

Abstract

BackgroundInsulin-like growth factor-1 (IGF-1) is a polypeptide growth factor with a variety of functions in both neuronal and non-neuronal cells. IGF-1 plays anti-apoptotic and other functions by activating multiple signaling pathways including Akt kinase, a serine/threonine kinase essential for cell survival. The nuclear transcription factor cAMP response element-binding protein (CREB) may also be involved although relationships between these two proteins in IGF-1 receptor signaling and protection is not clear, especially in neuronal cells.ResultsIGF-1, in a concentration- and time-dependent manner, induces the activation/phosphorylation of Akt and CREB in PC12 cells by activating different signaling pathways. IGF-1 induced a sustained phosphorylation of Akt while only a transient one was seen for CREB. The phosphorylation of Akt is mediated by the PI3 kinase pathway while that of CREB is dependent on the activation of both MAPK kinase and p38 MAPK. Moreover, the stimulation of PKC attenuated the phosphorylation of Akt induced by IGF-1 while enhancing that of CREB. Survival assays with various kinase inhibitors suggested that the activation/phosphorylation of both Akt and CREB contributes to IGF-1 mediated cell survival in PC12 cells.ConclusionThese data suggest that IGF-1 induced the activation of Akt and CREB using distinct pathways in PC12 cells.

Highlights

Insulin-like growth factor-1 (IGF-1) is a polypeptide growth factor with a variety of functions in both neuronal and non-neuronal cells
Several kinases including cyclic AMP-dependent protein kinase (PKA), protein kinase-C (PKC), calcium/calmodulin-dependent protein kinases, MAPK/p38 MAPK/MAPKAP kinase-2, ribosomal S6 kinase (RSK) family of kinases, the mitogen and stressactivated protein kinases 1 (MSK1) and Akt have been shown to be capable of phosphorylating this protein on Ser-133 residue [28,33,34,35,36,37,38]
IGF-1 stimulates the phosphorylation of Akt and cAMP response element-binding protein (CREB) in PC12 cells To investigate the effect of IGF-1 on the activation/phosphorylation of Akt and CREB in neuronal cells, PC12 cells were treated with 1–100 nM IGF-1 and the phosphorylation of Akt and CREB evaluated as described in Methods

Summary

Introduction

Insulin-like growth factor-1 (IGF-1) is a polypeptide growth factor with a variety of functions in both neuronal and non-neuronal cells. Activated receptor kinase phosphorylates various intracellular proteins like the insulin receptor substrate-1 (IRS-1) and Shc [3,4,5], leading to the activation of multiple signaling pathways including the phosphatidylinositide 3 kinase (PI3K)/Akt pathways and the mitogen-activated protein (MAP) kinase ( (page number not for citation purposes). BMC Neuroscience 2006, 7:51 http://www.biomedcentral.com/1471-2202/7/51 development, memory consolidation, and neuroprotection [24,25,26,27,28,29,30] This transcriptional factor belongs to the CREB/ATF family and binds to the specific sequence, 5'TGACGTCA-3' known as CRE [31]. Activation of this transcription factor requires the phosphorylation of the Ser133 residue which increases its association with CREBbinding protein [32]. Several kinases including cyclic AMP-dependent protein kinase (PKA), protein kinase-C (PKC), calcium/calmodulin-dependent protein kinases, MAPK/p38 MAPK/MAPKAP kinase-2, ribosomal S6 kinase (RSK) family of kinases, the mitogen and stressactivated protein kinases 1 (MSK1) and Akt have been shown to be capable of phosphorylating this protein on Ser-133 residue [28,33,34,35,36,37,38]

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Results

Discussion

Conclusion