scholarly journals Direct interaction of insulin-like growth factor-1 receptor with leukemia-associated RhoGEF

2001 ◽  
Vol 155 (5) ◽  
pp. 809-820 ◽  
Author(s):  
Shinichiro Taya ◽  
Naoyuki Inagaki ◽  
Hiroaki Sengiku ◽  
Hiroshi Makino ◽  
Akihiro Iwamatsu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pdz Domain ◽  
Ectopic Expression ◽  
Rho Kinase ◽  
Direct Interaction ◽  
Stress Fibers ◽  
Insulin Like Growth Factor ◽  
Nucleotide Exchange

Insulin-like growth factor (IGF)-1 plays crucial roles in growth control and rearrangements of the cytoskeleton. IGF-1 binds to the IGF-1 receptor and thereby induces the autophosphorylation of this receptor at its tyrosine residues. The phosphorylation of the IGF-1 receptor is thought to initiate a cascade of events. Although various signaling molecules have been identified, they appear to interact with the tyrosine-phosphorylated IGF-1 receptor. Here, we identified leukemia-associated Rho guanine nucleotide exchange factor (GEF) (LARG), which contains the PSD-95/Dlg/ZO-1 (PDZ), regulator of G protein signaling (RGS), Dbl homology, and pleckstrin homology domains, as a nonphosphorylated IGF-1 receptor-interacting molecule. LARG formed a complex with the IGF-1 receptor in vivo, and the PDZ domain of LARG interacted directly with the COOH-terminal domain of IGF-1 receptor in vitro. LARG had an exchange activity for Rho in vitro and induced the formation of stress fibers in NIH 3T3 fibroblasts. When MDCKII epithelial cells were treated with IGF-1, Rho and its effector Rho-associated kinase (Rho-kinase) were activated and actin stress fibers were enhanced. Furthermore, the IGF-1–induced Rho-kinase activation and the enhancement of stress fibers were inhibited by ectopic expression of the PDZ and RGS domains of LARG. Taken together, these results indicate that IGF-1 activates the Rho/Rho-kinase pathway via a LARG/IGF-1 receptor complex and thereby regulates cytoskeletal rearrangements.

scholarly journals O efeito molecular e estrutural do hormônio tiroideano no esqueleto

2004 ◽  
Vol 48 (1) ◽  
pp. 183-195 ◽  
Author(s):  
Cecília H.A. Gouveia
Keyword(s):  
Growth Factor ◽  
Insulin Like Growth Factor ◽  
Receptores Nucleares

O hormônio tiroideano é essencial para o desenvolvimento, maturação e metabolismo ósseos normais. Durante o desenvolvimento, a deficiência do hormônio tiroideano resulta em atraso na maturação do esqueleto e disgênese das epífises, resultando em redução do crescimento e anormalidades esqueléticas. O hormônio tiroideano também tem efeito no osso do adulto. A tirotoxicose é freqüentemente associada ao aumento do metabolismo ósseo e diminuição da massa óssea. Embora a importância do hormônio tiroideano no desenvolvimento e metabolismo ósseos seja clara, os mecanismos que medeiam os efeitos desse hormônio no tecido ósseo apenas começam a ser desvendados. O hormônio tiroideano pode atuar indiretamente no esqueleto, aumetando a secreção de hormônio do crescimento (GH) e insulin-like growth factor-1 (IGF-1); ou diretamente, modulando genes alvo via receptores nucleares específicos. Não se sabe, entretanto, se os principais efeitos do hormônio tiroideano no osso são resultado de ações diretas ou indiretas. Achados in vitro, tais como a presença de receptores de hormônio tiroideano (TR) e a indução de genes e proteínas em células esqueléticas pelo hormônio tiroideano, evidenciam a importância de ações diretas. Esta revisão tem como meta sumarizar os achados in vivo e in vitro relacionados aos efeitos do hormônio tiroideano no esqueleto.

Transport of Insulin-Like Growth Factor 1 in Intervertebral Disc: Effect of Binding Interactions and Inhomogeneous Distribution of Binding Proteins in Annulus Fibrosus and Nucleus Pulposus

2010 ◽  
Author(s):  
Francesco Travascio ◽  
Chun Yuh Huang ◽  
Wei Yong Gu
Keyword(s):  
Growth Factor ◽  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Reactive Transport ◽  
Binding Proteins ◽  
Insulin Like Growth Factor ◽  
Igf Binding Proteins ◽  
Binding Interactions

The intervertebral disc (IVD), being the largest avascular structure in human body, receives nourishment from the vascular network present near its periannular surface and at cartilage endplates (CEPs). It is believed that insufficient nutritional supply is a major cause for disc degeneration [1]. Understanding the mechanisms of solute transport in IVD is crucial for elucidating the etiology of disc degeneration, and to develop strategies for tissue repair (in vivo), and tissue engineering (in vitro). Transport in IVD is complex and involves a series of electromechanical, chemical, and biological coupled events. This study focused on the implications of solute-tissue reversible binding reactions on transport phenomena in the disc. A two dimensional (2D) finite element model was developed to predict diffusive-reactive transport in IVD. The numerical model was used to simulate transport of insulin-like growth factor 1 (IGF-1) in IVD, in the presence of binding interactions between IGF-1 and IGF-binding proteins (IGFBP-3) located on the extracellular matrix (ECM) of the disc.

scholarly journals Modulation of 11β-Hydroxysteroid Dehydrogenase Isozymes by Growth Hormone and Insulin-Like Growth Factor: In Vivo and In Vitro Studies1

1999 ◽  
Vol 84 (11) ◽  
pp. 4172-4177 ◽  
Author(s):  
J. S. Moore ◽  
J. P. Monson ◽  
G. Kaltsas ◽  
P. Putignano ◽  
P. J. Wood ◽  
...  
Keyword(s):  
Growth Factor ◽  
Reductase Activity ◽  
Primary Cultures ◽  
Inverse Correlation ◽  
Hydroxysteroid Dehydrogenase ◽  
Insulin Like Growth Factor ◽  
Igf I ◽  
Glucose Output

The interconversion of hormonally active cortisol (F) and inactive cortisone (E) is catalyzed by two isozymes of 11β-hydroxysteroid dehydrogenase (11βHSD), an oxo-reductase converting E to F (11βHSD1) and a dehydrogenase (11βHSD2) converting F to E. 11βHSD1 is important in mediating glucocorticoid-regulated glucose homeostasis and regional adipocyte differentiation. Earlier studies conducted with GH-deficient subjects treated with replacement GH suggested that GH may modulate 11βHSD1 activity. In 7 acromegalic subjects withdrawing from medical therapy (Sandostatin-LAR; 20–40 mg/month for at least 12 months), GH rose from 7.1 ± 1.5 to 17.5 ± 4.3 mU/L (mean ± se), and insulin-like growth factor I (IGF-I) rose from 43.0 ± 8.8 to 82.1 ± 13.7 nmol/L (both P < 0.05) 4 months after treatment. There was a significant alteration in the normal set-point of F to E interconversion toward E. The fall in the urinary tetrahydrocortisols/tetrahydocortisone ratio (THF+allo-THF/THE; 0.82 ± 0.06 to 0.60 ± 0.06; P < 0.02) but unaltered urinary free F/urinary free E ratio (a marker for 11βHSD2 activity) suggested that this was due to inhibition of 11βHSD1 activity. An inverse correlation between GH and the THF+allo-THF/THE ratio was observed (r = −0.422; P < 0.05). Conversely, in 12 acromegalic patients treated by transsphenoidal surgery (GH falling from 124 ± 49.2 to 29.3 ± 15.4 mU/L; P < 0.01), the THF+allo-THF/THE ratio rose from 0.53 ± 0.06 to 0.63 ± 0.07 (P < 0.05). Patients from either group who failed to demonstrate a change in GH levels showed no change in the THF+allo-THF/THE ratio. In vitro studies conducted on cells stably transfected with either the human 11βHSD1 or 11βHSD2 complementary DNA and primary cultures of human omental adipose stromal cells expressing only the 11βHSD1 isozyme indicated a dose-dependent inhibition of 11βHSD1 oxo-reductase activity with IGF-I, but not GH. Neither IGF-I nor GH had any effect on 11βHSD2 activity. GH, through an IGF-I-mediated effect, inhibits 11βHSD1 activity. This reduction in E to F conversion will increase the MCR of F, and care should be taken to monitor the adequacy of function of the hypothalamo-pituitary-adrenal axis in acromegalic subjects and in GH-deficient, hypopituitary patients commencing replacement GH therapy. Conversely, enhanced E to F conversion occurs with a reduction in GH levels; in liver and adipose tissue this would result in increased hepatic glucose output and visceral adiposity, suggesting that part of the phenotype currently attributable to adult GH deficiency may be an indirect consequence of its effect on tissue F metabolism via 11βHSD1 expression.

scholarly journals Cytoplasmic p21Cip1/WAF1 regulates neurite remodeling by inhibiting Rho-kinase activity

2002 ◽  
Vol 158 (2) ◽  
pp. 321-329 ◽  
Author(s):  
Hiroyuki Tanaka ◽  
Toshihide Yamashita ◽  
Minoru Asada ◽  
Shuki Mizutani ◽  
Hideki Yoshikawa ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Developmental Process ◽  
Ectopic Expression ◽  
Rho Kinase ◽  
Nuclear Antigen ◽  
Nih3t3 Cells ◽  
Localization Signal ◽  
Newborn Neurons

p21Cip1/WAF1 has cell cycle inhibitory activity by binding to and inhibiting both cyclin/Cdk kinases and proliferating cell nuclear antigen. Here we show that p21Cip1/WAF1 is induced in the cytoplasm during the course of differentiation of chick retinal precursor cells and N1E-115 cells. Ectopic expression of p21Cip1/WAF1 lacking the nuclear localization signal in N1E-115 cells and NIH3T3 cells affects the formation of actin structures, characteristic of inactivation of Rho. p21Cip1/WAF1 forms a complex with Rho-kinase and inhibits its activity in vitro and in vivo. Neurite outgrowth and branching from the hippocampal neurons are promoted if p21Cip1/WAF1 is expressed abundantly in the cytoplasm. These results suggest that cytoplasmic p21Cip1/WAF1 may contribute to the developmental process of the newborn neurons that extend axons and dendrites into target regions.

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