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
© Zheng and Quirion; licensee BioMed Central Ltd. 2006
Received: 21 December 2005
Accepted: 22 June 2006
Published: 22 June 2006
Insulin-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.
IGF-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.
These data suggest that IGF-1 induced the activation of Akt and CREB using distinct pathways in PC12 cells.
Insulin-like growth factor-1 (IGF-1) is a polypeptide trophic factor playing important roles in the survival and differentiation of both neuronal and non-neuronal cells [1, 2]. The biological actions of IGF-1 are mediated by a heterotetrameric tyrosine kinase receptor, the IGF-1 receptor, which is similar to the insulin receptor both in structure and functions [2, 3]. Binding of IGF-1 to its receptor causes receptor autophosphorylation and the activation of intrinsic tyrosine kinase. Activated receptor kinase phosphorylates various intracellular proteins like the insulin receptor substrate-1 (IRS-1) and Shc [3–5], leading to the activation of multiple signaling pathways including the phosphatidylinositide 3 kinase (PI3K)/Akt pathways and the mitogen-activated protein (MAP) kinase (also called extracellular signal-regulated kinase; ERK; [2, 3, 6, 7]).
Akt, a key target of the PI3 kinase, is a serine/threonine kinase that plays critical roles in the modulation of cell development, growth and survival [8–10]. Stimulation of cells with IGF-1 induces the activation of PI3 kinase leading to increased levels of phosphatidylinositol [3, 4] diphosphate [PI [3, 4] P2] and phosphatidylinositol [3–5] triphosphate [PI [3–5] P3] in target cells [11, 12]. This event recruits Akt to the plasma membrane where it is phosphorylated by PI [3–5] P3 dependent kinase, (PDK)-1 and -2, respectively at residues Thr308 and Ser473 [13, 14]. The phosphorylation of these residues activates Akt kinase which can then phosphorylate its many substrates including glycogen synthase kinase-3 (GSK-3) , the Bcl-2 family member Bad , caspase-9 , nuclear factor-κB (NFκB) [18, 19] and the winged-helix family of transcription factors, FOXO1, FOXO3a and FOXO4 [1, 10, 20–22], leading to cell survival and the inhibition of apoptosis [1, 8, 10, 23].
The Ca2+/cyclic AMP response element-binding protein (CREB) is one of the common nuclear targets of tyrosine kinase receptors playing important roles in many biological functions including neuronal plasticity, full axonal development, memory consolidation, and neuroprotection [24–30]. This transcriptional factor belongs to the CREB/ATF family and binds to the specific sequence, 5'-TGACGTCA-3' known as CRE . Activation of this transcription factor requires the phosphorylation of the Ser-133 residue which increases its association with CREB-binding protein . 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 stress-activated protein kinases 1 (MSK1) and Akt have been shown to be capable of phosphorylating this protein on Ser-133 residue [28, 33–38].
IGF-I stimulates the phosphorylation of CREB and regulates the expression of a number of CRE-containing genes including bcl-2 and c-fos in several cell types [32, 39]. Interestingly, CREB is reported as a possible target of Akt [30, 37] suggesting that it may be a target of Akt in IGF-1 mediated survival. However, reports about Akt as a CREB kinase in IGF-1 signalling is still rather controversial with one report suggesting that the phosphorylation of CREB induced by IGF-1 is independent on Akt . Moreover, the signalling of CREB and Akt is cell type-dependent and effectors specific . Therefore, it is deemed important to clarify the role of Akt in the phosphorylation of CREB induced by IGF-1. Accordingly, we characterized here the signalling of IGF-1 stimulated activation of CREB compared to that of the PI3K/Akt in PC12 cells. Our data show that IGF-1 promotes the phosphorylation of Akt and CREB in these cells. The activation of Akt is mainly mediated by the PI3 kinase pathway, while that of CREB is primarily dependent on the activation of MAPK and p38-MAP kinases revealing the differential regulation of these two proteins by IGF-1 receptor signalling. It also argues against a key role for Akt as a CREB kinase in PC12 cells. The survival study suggests that the activation of these two proteins likely contributes to the survival effects of IGF-1 in PC12 cells, with the PI3K/Akt kinase pathway playing a predominant role.
IGF-1 stimulates the phosphorylation of Akt and CREB in PC12 cells
The phosphorylation of Akt by IGF-1 is mediated by PI3 kinase while MAPK and p38 MAPK regulate IGF-1 induced phosphorylation of CREB
To extend these results further, wortmannin, another well known PI3 kinase inhibitor, was investigated in our model. Wortmannin (100 nM) had no effect on IGF-1 stimulated phosphorylation of CREB but most significantly blocked that of Akt demonstrating further the differential mechanisms used by IGF-1 to regulate their phosphorylation (Figure 3B).
MAPK kinase and p38 MAP kinase inhibitors concentration-dependently inhibit IGF-1-induced phosphorylation of CREB
PMA attenuates IGF-1-induced phosphorylation of Akt while increasing CREB phosphorylation
Treatment with a tyrosine kinase inhibitor blocks IGF-1 receptor signaling, including the phosphorylation of Akt and CREB
Both Akt and CREB can contribute to the survival effects of IGF-1 in PC12 cells
Effects of other trophic factors and agents in the phosphorylation of CREB
The present study demonstrates that IGF-1 is able to time- and concentration-dependently stimulates the activation of both Akt and CREB in PC12 cells. The activation of Akt by IGF-1 is mediated by the PI3 kinase pathway while MAPK and p38 MAPK are involved in IGF-1 induced phosphorylation of CREB. Survival assay revealed that these various pathways contribute to the survival effects of IGF-1 in PC12 cells.
IGF-I is a polypeptide trophic factor capable of supporting growth and of preventing death in neuronal and non-neuronal cells. The biological functions of this growth factor are mediated by IGF-I receptors. Recent studies have shown that both IGF-1 and its receptors are expressed in the CNS [1, 21, 43], and their respective expression is upregulated in response to injuries [1, 44]. It is also well established that IGF-1 protects the brain from hypoxic and ischemic injuries . IGF-1 is also neuroprotective in a broad range of cells including cultured primary hippocampal neurons. These neuroprotective effects likely involve multiple signaling pathways but in particular the PI3K/Akt kinase and MAPK-CREB pathways [2, 30, 46, 47]. Consistent with these findings, our results show here that IGF-1 is able to stimulate the activation of both the PI3K/Akt kinase and MAPK-CREB pathways in PC12 cells.
Although mechanisms underlying the phosphorylation of CREB have been extensively studied, the role of a given signaling pathway in mediating the effect of a trophic factor on CREB remains somewhat controversial. For example, while Akt has been suggested to act as a 'CREB kinase', data obtained here are not fully supportive of such an hypothesis. Indeed while IGF-1 induced the sustained phosphorylation of Akt, only a transient one was seen for CREB. Moreover, inhibitors of PI3K/Akt blocked the activation/phopsphorylation of Akt with almost no effect on the phosphorylation of CREB. In contrast, MAPK and p38 kinase inhibitors significantly diminished IGF-1-induced phosphorylation of CREB while only having a small effect on Akt. Indeed, the MAPK pathway inhibitor PD98059 and the p38 MAPK kinase inhibitor, PD169316, at concentrations fully inhibiting MAPK and p38 kinase respectively, significantly abrogated the phosphorylation of CREB while having no significant effect on the activation of Akt. Moreover, the phosphorylation of CREB induced by IGF-1 is not inhibited by Akt inhibitors at concentrations that fully blocked the phosphorylation of GSK3β, a target of Akt in the IGF-1 signaling pathway (data not shown). Finally, PMA, an activator of PKC, attenuated IGF-1-induced activation of Akt while enhancing the phosphorylation of CREB. Taken together, these data reveal that IGF-1-induced phosphorylation of Akt and CREB is mediated via distinct pathways and suggest that CREB is not a direct substrate of Akt in IGF-1 receptor signaling in PC12 cells.
In fact, MAPK and p38 MAPK most likely contribute to the phosphorylation of CREB stimulated by IGF-1 in PC12 cells. However, the existence of kinase(s) which can actually phosphorylate CREB at Ser-133 has not been reported in PC12 cells. MAPK and p38 MAPK cannot directly phosphorylate CREB at this residue as it is not a proline-directed phosphorylation site . Downstream targets of these two kinases that may be able to phosphorylate CREB in PC12 cells include the ribosomal S6 kinase (RSK) family of kinases, MAPKAP kinase 2/3 and MSK1/2. For example, the over-expression of inhibitory RSK2 mutants reduced EGF-induced CREB phosphorylation  while cells deficient for this kinase were found to be resistant to EGF-stimulated CREB phosphorylation . However, Rsk-2-deficient cell lines have shown that this kinase is not essential for the activation of CREB in response to PDGF and IGF-1 .
MAPKAP kinase-2, an enzyme immediately downstream of p38 MAP kinase, is able to phosphorylate CREB at Ser133 in vitro, and has been suggested to play an important role in FGF- or stress-induced phosphorylation of CREB and ATF-1 in SK-N-MC cells . However, a subsequent report using PC12, HeLa and SK-N-MC cell lines failed to demonstrate a role for both RSK2 and MAPKAP-2/3 as CREB kinases in signalling induced by TNF, NGF and FGF . The potential role of this kinase in IGF-1 induced CREB phosphorylation in PC12 cells hence remains to be fully established.
MSK1 is a downstream kinase of the MAPK and p38 MAPK kinase pathways and is important in stress and mitogen-induced CREB phosphorylation in fibroblasts, PC12 cells and embryonic stem cells [38, 50–52]. Since both MAPK and p38 MAPK are involved in IGF-1 induced phosphorylation of CREB in PC12 cells, MSK1 is thus a possible intermediate step. Consistent with this hypothesis, preliminary data have shown that blockade of MSK1 significantly inhibited IGF-1 stimulated phosphorylation of CREB in PC12 cells (Zheng and Quirion, unpublished results).
The biological significance of the finding that distinct pathways are involved in IGF-1 induced phosphorylation of Akt and CREB is not clear. Both proteins are known to play central roles in cell survival [9, 46, 47, 53]. The role of Akt in cell survival was proposed first by Dudek and colleagues (1997) in a study showing that IGF-1-induced survival of cultured cerebellar granule cells was mediated by this kinase . Subsequently, Akt was shown to be a key survival promoting kinase for a broad of range of factors in a variety of cell type [1, 22, 46, 47]. It is known that activated Akt can phosphorylate and hence inactivate proapoptotic proteins such as the Bcl-2 family member Bad , caspase-9 , GSK3 , FOXO transcription factors [21, 22, 47] and ASK1 . Akt can also affect the expression of Bcl-2 family members in target cells as well as the function of NF-kappaB and CREB [46, 47].
The MAPK-CREB pathway was also reported to play a major role in neuronal survival including in PC12 cells [47, 53]. For example, MAPK can activate RSKs and MSK1/2 [51, 53]. RSKs are then able to phosphorylate the pro-apoptotic protein Bad at Ser- 112suppressing Bad-mediated apoptosis . RSKs and possibly MSK1/2 are also able to facilitate the phosphorylation of CREB at Ser-133, leading to cell survival. Accordingly, the Akt and MAPK-CREB pathways likely have additive effects in contributing to the survival effects induced by IGF-1 in PC12 cells. This is also exemplified by the action of Akt and MAPK in the phosphorylation of Bad. In the presence of growth factors, Akt is activated and phosphorylates Bad at Ser-136, inhibiting its pro-apoptotic effect . In parallel, the activation of MAPK leads to the phosphorylation of Ser-112 further inhibiting Bad . Hence, IGF-1 by acting via the IGF-1 receptor complex and parallel downstream effectors can inhibit various pro-apoptotic signals in a variety of cells including PC12 cells.
In conclusion, this study shows that IGF-1-induced phosphorylation of Akt kinase is mediated by the PI3 kinase pathway while that of CREB is regulated mainly by activating the MAPK and p38 MAPK pathways.
Human recombinant IGF-1 was obtained as a gift from Genentech Inc (San Francisco, CA). LY294002, PD98059, herbimycin A, rapamycin, PD169316, Akt inhibitors I and II were purchased from Calbiochem (Bad Soden, Germany) whereas wortmannin, leupeptin, aprotinin, sodium vanadate and phorbol 12-myristate 13-acetate (PMA) were from Sigma Chemical (St Louis, MO). U0126 was purchased from Promega (Madison, WI). Anti-phospho-CREB-133, anti-CREB, anti-phospho-p38 MAPK, anti-phospho-Akt, anti-phopho-GSK3β (Ser-9) and anti-phospho-MAPK antibodies were obtained from Cell Signaling Technology (Beverly, MA). Anti-Akt, anti-MAPK, anti-p38 MAPK and all secondary antibodies conjugated with horseradish peroxidase (HRP) were from Santa Cruz Biotechnology (Santa Cruz, CA). Cell culture reagents were purchased from GIBCO Life Technologies (Grand Island, NY) whereas all other reagents were from Sigma Chemical or Fisher Scientific (Nepean, ON).
PC12 cells were kindly provided by Dr. Gordon Guroff at NICHD, NIH (Betheda, MD) and cultured as described before. In brief, PC12 cells were maintained in 75 cm2 flasks in high glucose Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 5% (vol/vol) fetal bovine serum (FBS), 5% horse serum, 100 μg streptomycin/ml and 100 U penicillin/ml. Cells were incubated at 37°C with 5% CO2 humidified atmosphere. Stock culture was routinely sub-cultured at 1:5 ratio at a week interval.
Before each experiment, cells were detached using 5 mM EDTA in Hank's balance buffer (HBS) and seeded in 12 or 6 well plates (coated with poly-D-lysine, 10 μg/ml) at a density of 3–6 × 105cells/well in 2% serum medium for 24 hrs. Culture medium was replaced with DMEM 2 hr before the desired reagents were added. To study the effect of IGF-1 on the phosphorylation of Akt, CREB, MAPK, p38 MAPK and GSK3beta, cells were treated with 10 nM IGF-1 for 10 min. Alternatively, cells were pretreated with wortmannin (0–2 μM, 30 min), LY294002 (6–50 μM, 30 min), rapamycin (50 nM, 30 min), PD98059 (6–50 μM, 40 min) or PD169316 (2.5–20 μM, 40 min) followed by a stimulation with 10 nM IGF-1. For the experiments with PKC, 400 nM PMA was added to cells 2.5 min prior to IGF-1 stimulation.
Western blotting was performed as described earlier with some modifications [1, 23]. Briefly, treated cells from different experimental conditions were rinsed twice with ice cold HBSS and lysed in either sample buffer [62.5 mM Tris-HCl, pH 6.8, 2% w/v sodium dodecyl sulfate (SDS), 10% glycerol, 50 mM dithiothreitol (DTT) and 0.1% w/v bromphenol blue] or RIPA buffer [50 mM Tris-HCl, pH 8.0, 150 mM NaCl, 1 mM EDTA, 1% Igepal CA-630, 0.1% SDS, 50 mM NaF, 1 mM NaVO3, 5 mM phenyl-methylsulfonyl fluoride, 10 μg/ml leupeptin, 10 μg/ml aprotinin]. Samples with equal amounts of protein were then separated by 4–20% polyacrylamide gel electrophoresis (PAGE), and the resolved proteins were electrotransferred to Hybond-C Nitrocellulose. Membranes were incubated with 5% non-fat milk in TBST (10 mM Tris-HCl, pH 8.0, 150 mM NaCl and 0.2% Tween-20) for 1 hr at room temperature and incubated with appropriate primary antibody at 4°C overnight. Membranes were then washed twice with TBST and probed with corresponding second antibodies conjugated with HRP (anti/rat/mouse/rabbit/goat-HRP) at room temperature for 1 hr. Membranes were finally washed several times with TBST to remove unbound secondary antibodies and visualized using an ECL detection kit (Amersham Co, Toronto, ON). A part of the SDS gel was stained with Coomassie Blue to ensure the use of equal amounts of protein.
The respective phosphorylation of Akt, MAPK, CREB, GSK3β (Ser-9) and p38 MAPK was determined by Western blot using anti-phospho-Akt, anti-phospho-MAPK, anti-phospho-CREB, anti-phopho-GSK3β (Ser-9) and anti-phospho-p38 MAPK antibodies, respectively. Blots were stripped and reprobed with anti-Akt, anti-MAPK, CREB, GSK3β and p38 MAPK antibodies to ensure that equal amounts of various proteins were present. The effect of IGF-1 was determined by comparing the phosphorylation of above protein and their unphosphorylated counterpart or beta-actin levels in cell extracts determined as mentioned above.
Determination of tyrosine phosphorylation of the IGF-1 receptor, IRS-1 and their interactions with PI3 kinase was established by immunoprecipitation
PC12 cells were treated with 10 nM IGF-1 for 8 min and rinsed with cold phosphate buffer saline (PBS). After centrifugation at 1000 g for 5 min at 4°C, cell pellets were lysed on ice in pre-cold RIPA buffer for 20 min. Cell lysates were then pelleted at 13,000 g for 10 min and the concentration of protein in each sample was determined using the Bio-Red dye-binding method with bovine serum albumin (BSA) as standard. The supernatant with equal amount of protein was incubated overnight at 4°C with either anti-IGF-1R, anti-IRS-1 or anti-PI3 kinase antibodies. Formed immunocomplexes were isolated by protein A/G PLUS-agarose (Santa Cruz Biotechnology, Inc.), separated by 4–20% SDS gel and then tyrosine phosphorylation was determined by Western blot with a mixture of anti-phosphotyrosine antibodies 4G10 and PY99. Blots were striped and reprobed with PI3 kinase or IRS-1 antibodies to evaluate the interaction of IGF-1R and IRS-1 with PI3 kinase. Finally, the blots were reprobed with anti-IGF-1R, anti-IRS-1 or anti-PI3 kinase to ensure the presence of equal amount of proteins.
Cell viability using the MTT assay
PC12 cells (10000 to 20000 cells/well) in serum -free medium DMEM or DMEM supplemented with 1 % FBS were added to 96- well plates and incubated at 37°C with 5% CO2 for 1 h. Cells were pretreated with 25 μM LY294002, 25 μM PD98059, 10 μM PD169316 for 40 min and then 1 % FBS and 10 nM IGF-1 for 24–48 hours. Following replacement of the medium with 0.5 mg/ml MTT in DMEM, cells were returned into the incubator for a 3-hr period. Cells and MTT formazan crystals were then solubilized by trituration in a solution of isopropanol/HCL (0.1 N) and the survival profile of these cells were quantified by spectrophotometrically measuring the plate at 570 nM. Assays were repeated at least three to six times, each in quadruplicate.
Data are expressed as mean ± SEM. A one-way ANOVA with Newman-Keul test was used to establish statistical significance set at p < 0.05.
This research was supported by the Canadian Institutes of Health Research
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