scholarly journals Astrocyte resilience to oxidative stress induced by insulin-like growth factor I (IGF-I) involves preserved AKT (protein kinase B) activity.

2016 ◽  
Vol 291 (23) ◽  
pp. 12039-12039 ◽  
Author(s):  
David Dávila ◽  
Silvia Fernández ◽  
Ignacio Torres-Alemán
Keyword(s):  
Oxidative Stress ◽  
Growth Factor ◽  
Protein Kinase ◽  
Protein Kinase B ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

scholarly journals Astrocytes require insulin-like growth factor I to protect neurons against oxidative injury

F1000Research ◽  
2014 ◽  
Vol 3 ◽  
pp. 28 ◽  
Author(s):  
Laura Genis ◽  
David Dávila ◽  
Silvia Fernandez ◽  
Andrea Pozo-Rodrigálvarez ◽  
Ricardo Martínez-Murillo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Growth Factor ◽  
Brain Aging ◽  
Oxidative Injury ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Brain Responses ◽  
Igf I ◽  
Growth Factor I

Oxidative stress is a proposed mechanism in brain aging, making the study of its regulatory processes an important aspect of current neurobiological research. In this regard, the role of the aging regulator insulin-like growth factor I (IGF-I) in brain responses to oxidative stress remains elusive as both beneficial and detrimental actions have been ascribed to this growth factor.Because astrocytes protect neurons against oxidative injury, we explored whether IGF-I participates in astrocyte neuroprotection and found that blockade of the IGF-I receptor in astrocytes abrogated their rescuing effect on neurons. We found that IGF-I directly protects astrocytes against oxidative stress (H2O2). Indeed, in astrocytes but not in neurons, IGF-I decreases the pro-oxidant protein thioredoxin-interacting protein 1 and normalizes the levels of reactive oxygen species. Furthermore, IGF-I cooperates with trophic signals produced by astrocytes in response to H2O2 such as stem cell factor (SCF) to protect neurons against oxidative insult. After stroke, a condition associated with brain aging where oxidative injury affects peri-infarcted regions, a simultaneous increase in SCF and IGF-I expression was found in the cortex, suggesting that a similar cooperative response takes place in vivo. Cell-specific modulation by IGF-I of brain responses to oxidative stress may contribute in clarifying the role of IGF-I in brain aging.

scholarly journals RACK1, an Insulin-Like Growth Factor I (IGF-I) Receptor-Interacting Protein, Modulates IGF-I-Dependent Integrin Signaling and Promotes Cell Spreading and Contact with Extracellular Matrix

2002 ◽  
Vol 22 (7) ◽  
pp. 2345-2365 ◽  
Author(s):  
Ulrich Hermanto ◽  
Cong S. Zong ◽  
Weiqun Li ◽  
Lu-Hai Wang
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Protein Kinase ◽  
Focal Adhesion ◽  
Cell Spreading ◽  
Β1 Integrin ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

ABSTRACT The insulin-like growth factor I (IGF-I) receptor (IGF-IR) is known to regulate a variety of cellular processes including cell proliferation, cell survival, cell differentiation, and cell transformation. IRS-1 and Shc, substrates of the IGF-IR, are known to mediate IGF-IR signaling pathways such as those of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K), which are believed to play important roles in some of the IGF-IR-dependent biological functions. We used the cytoplasmic domain of IGF-IR in a yeast two-hybrid interaction trap to identify IGF-IR-interacting molecules that may potentially mediate IGF-IR-regulated functions. We identified RACK1, a WD repeat family member and a Gβ homologue, and demonstrated that RACK1 interacts with the IGF-IR but not with the closely related insulin receptor (IR). In several types of mammalian cells, RACK1 interacted with IGF-IR, protein kinase C, and β1 integrin in response to IGF-I and phorbol 12-myristate 13-acetate stimulation. Whereas most of RACK1 resides in the cytoskeletal compartment of the cytoplasm, transformation of fibroblasts and epithelial cells by v-Src, oncogenic IR or oncogenic IGF-IR, but not by Ros or Ras, resulted in a significantly increased association of RACK1 with the membrane. We examined the role of RACK1 in IGF-IR-mediated functions by stably overexpressing RACK1 in NIH 3T3 cells that expressed an elevated level of IGF-IR. RACK1 overexpression resulted in reduced IGF-I-induced cell growth in both anchorage-dependent and anchorage-independent conditions. Overexpression of RACK1 also led to enhanced cell spreading, increased stress fibers, and increased focal adhesions, which were accompanied by increased tyrosine phosphorylation of focal adhesion kinase and paxillin. While IGF-I-induced activation of IRS-1, Shc, PI3K, and MAPK pathways was unaffected, IGF-I-inducible β1 integrin-associated kinase activity and association of Crk with p130CAS were significantly inhibited by RACK1 overexpression. In RACK1-overexpressing cells, delayed cell cycle progression in G1 or G1/S was correlated with retinoblastoma protein hypophophorylation, increased levels of p21Cip1/WAF1 and p27Kip1, and reduced IGF-I-inducible Cdk2 activity. Reduction of RACK1 protein expression by antisense oligonucleotides prevented cell spreading and suppressed IGF-I-dependent monolayer growth. Our data suggest that RACK1 is a novel IGF-IR signaling molecule that functions as a positive mediator of cell spreading and contact with extracellular matrix, possibly through a novel IGF-IR signaling pathway involving integrin and focal adhesion signaling molecules.

Protein Kinase B Is Expressed in Pancreatic β Cells and Activated upon Stimulation with Insulin-like Growth Factor I

1998 ◽  
Vol 250 (1) ◽  
pp. 181-186 ◽  
Author(s):  
Lena Stenson Holst ◽  
Hindrik Mulder ◽  
Vincent Manganiello ◽  
Frank Sundler ◽  
Bo Ahrén ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Protein Kinase B ◽  
Insulin Like Growth Factor ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Factor I ◽  
Growth Factor I

scholarly journals Neuronal Death by Oxidative Stress Involves Activation of FOXO3 through a Two-Arm Pathway That Activates Stress Kinases and Attenuates Insulin-like Growth Factor I Signaling

2008 ◽  
Vol 19 (5) ◽  
pp. 2014-2025 ◽  
Author(s):  
David Dávila ◽  
Ignacio Torres-Aleman
Keyword(s):  
Oxidative Stress ◽  
Growth Factor ◽  
P38 Mapk ◽  
Neuronal Death ◽  
Wide Spectrum ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Jun Kinase ◽  
Igf I ◽  
Growth Factor I

Oxidative stress kills neurons by stimulating FOXO3, a transcription factor whose activity is inhibited by insulin-like growth factor I (IGF-I), a wide-spectrum neurotrophic signal. Because recent evidence has shown that oxidative stress blocks neuroprotection by IGF-I, we examined whether attenuation of IGF-I signaling is linked to neuronal death by oxidative stress, as both events may contribute to neurodegeneration. We observed that in neurons, activation of FOXO3 by a burst of oxidative stress elicited by 50 μM hydrogen peroxide (H2O2) recruited a two-pronged pathway. A first, rapid arm attenuated AKT inhibition of FOXO3 through p38 MAPK-mediated blockade of IGF-I stimulation of AKT. A second delayed arm involved activation of FOXO3 by Jun-kinase 2 (JNK2). Notably, blockade of IGF-I signaling through p38 MAPK was necessary for JNK2 to activate FOXO3, unveiling a competitive regulatory interplay between the two arms onto FOXO3 activity. Therefore, an abrupt rise in oxidative stress activates p38 MAPK to tilt the balance in a competitive AKT/JNK2 regulation of FOXO3 toward its activation, eventually leading to neuronal death. In view of previous observations linking attenuation of IGF-I signaling to other causes of neuronal death, these findings suggest that blockade of trophic input is a common step in neuronal death.

Insulin-like growth factor I induces migration and invasion of human multiple myeloma cells

Blood ◽  
2004 ◽  
Vol 103 (1) ◽  
pp. 301-308 ◽  
Author(s):  
Ya-Wei Qiang ◽  
Lei Yao ◽  
Giovanna Tosato ◽  
Stuart Rudikoff
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Growth Factor ◽  
Protein Kinase ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Myeloma Cells ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

Abstract Multiple myeloma (MM) is an incurable form of cancer characterized by accumulation of malignant plasma cells in the bone marrow. During the course of this disease, tumor cells cross endothelial barriers and home to the bone marrow. In latter stages, myeloma cells extravasate through blood vessels and may seed a variety of organs. Insulin-like growth factor I (IGF-I) is one of several growth factors shown to promote the growth of MM cells. In the current study, we have assessed the ability of IGF-I to serve additionally as a chemotactic factor affecting the mobility and invasive properties of these cells. Results indicate that IGF-I promotes transmigration through vascular endothelial cells and bone marrow stromal cell lines. Analysis of endogenous signaling pathways revealed that protein kinase D/protein kinase Cμ (PKD/PKCμ) and RhoA were both activated in a phosphatidylinositol 3-kinase (PI-3K)–dependent manner. Inhibition of PI-3K, PKCs, or Rho-associated kinase by pharmacologic inhibitors abrogated migration, whereas mitogen-activated protein kinase (MAPK), Akt, and p70S6 kinase inhibitors had no effect. These results suggest that IGF-I promotes myeloma cell migration by activation of PI-3K/PKCμ and PI-3K/RhoA pathways independent of Akt. The identification of IGF-I as both a proliferative and migratory factor provides a rational basis for the development of targeted therapeutic strategies directed at IGF-I in the treatment of MM.

scholarly journals Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt.

1997 ◽  
Vol 17 (3) ◽  
pp. 1595-1606 ◽  
Author(s):  
G Kulik ◽  
A Klippel ◽  
M J Weber
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Tyrosine Kinases ◽  
Pi3 Kinase ◽  
Insulin Like Growth Factor ◽  
Phosphatidylinositol 3 Kinase ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I ◽  
Phosphatidylinositol 3

We have found that insulin-like growth factor I (IGF-I) can protect fibroblasts from apoptosis induced by UV-B light. Antiapoptotic signalling by the IGF-I receptor depended on receptor kinase activity, as cells overexpressing kinase-defective receptor mutants could not be protected by IGF-I. Overexpression of a kinase-defective receptor which contained a mutation in the ATP binding loop functioned as a dominant negative and sensitized cells to apoptosis. The antiapoptotic capacity of the IGF-I receptor was not shared by other growth factors tested, including epidermal growth factor (EGF) and thrombin, although the cells expressed functional receptors for all the agonists. However, EGF was antiapoptotic for cells overexpressing the EGF receptor, and expression of activated pp60v-src also was protective. There was no correlation between protection from apoptosis and activation of mitogen-activated protein kinase, p38/HOG1, or p70S6 kinase. On the other hand, protection by any of the tyrosine kinases against UV-induced apoptosis was blocked by wortmannin, implying a role for phosphatidylinositol 3-kinase (PI3 kinase). To test this, we transiently expressed constitutively active or kinase-dead PI3 kinase and found that overexpression of activated phosphatidylinositol 3-kinase (PI3 kinase) was sufficient to provide protection against apoptosis. Because Akt/PKB is believed to be a downstream effector for PI3 kinase, we also examined the role of this serine/threonine protein kinase in antiapoptotic signalling. We found that membrane-targeted Akt was sufficient to protect against apoptosis but that kinase-dead Akt was not. We conclude that the endogenous IGF-I receptor has a specific antiapoptotic signalling capacity, that overexpression of other tyrosine kinases can allow them also to be antiapoptotic, and that activation of PI3 kinase and Akt is sufficient for antiapoptotic signalling.

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