FSH & IGF-1 Synergistic Effect On Cartilage.Follicle-Stimulating Hormone Amplifies Insuline-like Growth Factor-1 (Longr3)

[Presser]

Follicle-stimulating hormone and insulin-like growth factor I synergistically induce up-regulation of cartilage link protein (Crtl1) via activation of phosphatidylinositol-dependent kinase/Akt in rat granulosa cells.

Sun GW1, Kobayashi H, Suzuki M, Kanayama N, Terao T.
Author information



Abstract

<abstracttext>FSH and IGF-I are both important determinants of follicle development and the process of cumulus cell-oocyte complex expansion. FSH stimulates the phosphorylation of Akt by mechanisms involving phosphatidylinositol 3-kinase (PI3-K), a pattern of response mimicking that of IGF-I. Cartilage link protein (Crtl1) is confined to the cartilaginous lineage and is assembled into a macroaggregate complex essential for hyaluronan-rich matrix stabilization. The present studies were performed to determine the actions of FSH and IGF-I on Crtl1 production in rat granulosa cells. Primary cultures of granulosa cells were prepared from 24-d-old rats. After treatments, cell extracts and media were prepared, and the Crtl1 level was determined by immunoblotting analysis using anti-Crtl1 antibodies. Here we showed that 1) treatment with FSH (> or = 25 ng/ml) or IGF-I (> or = 25 ng/ml) for 4 h increased Crtl1 production; 2) maximal stimulatory effects of FSH or IGF-I were observed at 100 or 50 ng/ml, respectively; 3) FSH caused a concentration-dependent increase in IGF-I-induced Crtl1 production and vice versa; 4) FSH and IGF-I also up-regulate the expression of Crtl1 mRNA; 5) FSH- and IGF-I-dependent Crtl1 production were abrogated by PI3-K inhibitors (LY294002 and wortmannin), and inhibition of Crtl1 production by p38 mitogen-activated protein kinase inhibitor (SB202190) was partial (approximately 30%), suggesting that PI3-K and, to a lesser extent, p38 mitogen-activated protein kinase are critical for the response. Our study represents the first report that FSH amplifies IGF-I-mediated Crtl1 production, possibly via PI3-K-Akt signaling cascades in rat granulosa cells.</abstracttext>

 

[Presser]

[h=1]The emerging role of insulin-like growth factors in testis development and function.[/h]Griffeth RJ1, Bianda V1, Nef S1.
[h=3]Author information[/h]

[h=3]Abstract[/h]in English, French
<abstracttext>The insulin-like family of growth factors (IGFs) - composed of insulin, and insulin-like growth factors I (IGF1) and II (IGF2) - provides essential signals for the control of testis development and function. In the testis, IGFs act in an autocrine-paracrine manner but the extent of their actions has been underestimated due to redundancies at both the ligand and receptor levels, and the perinatal lethality of constitutive knockout mice. This review synthesizes the current understanding of how the IGF system regulates biological processes such as primary sex determination, testis development, spermatogenesis and steroidogenesis, and highlights the questions that remain to be explored.</abstracttext>


[h=4]KEYWORDS:[/h]IGF-I; IGF-II; Insulin; Leydig cells; Sertoli cells; Sex determination; Spermatogenesis; Testis


[h=1]Figure 1[/h]

Receptors for insulin, IGF1 and IGF2. INSR and IGF1R are composed of two αβ dimers which associate to form heterotetrameric complexes. The αβ dimers are linked together by disulfide bonds and two dimers are also linked by disulfide bonds to form the tetramer. The α subunit is the extracellular portion of the receptor while the β subunit spans the membrane and its cytoplasmic portion interacts with IRS proteins which are key intracellular mediators of insulin/IGF signaling. Single αβ dimers are derived from separate genes and the INSR has two splice variants, INSR-B and INSR-A. Each variant shares the same membrane-spanning β subunit (dark blue) but differs in the extracellular α subunit (light pink or dark pink, respectively). The IGF1R has different α and β subunits compared to the INSR (dark green). These combinations of αβ dimers allow for hybrid receptors, which bind insulin, IGF1, and IGF2 with differing affinities. The schematic shows the αβ dimers, α2β2 hybrid receptors, and the known ligands that bind each receptor. Relative binding affinities are represented by arrows, where a solid arrow signifies a higher binding affinity than a broken arrow.




[h=1]Figure 2[/h]

A simplified view of insulin/IGF1 signaling. Insulin/IGF1 signaling is mediated by a complex, highly integrated network that controls several processes. Two major pathways are activated by insulin/IGF1 signaling, the ATK/PI3K pathway and the ERK/MAPK pathway, which are involved in several cellular processes such as metabolism, cell growth, proliferation, and apoptosis. Activation of the INSR/IGF1R by insulin/IGF1 binding leads to autophosphorylation of the β subunits and the receptor tyrosine kinase subsequently phosphorylates IRS proteins on their tyrosine residues. This creates recognition sites for additional effector molecules containing SH2 domains, such the p85 regulatory subunit of PI3K (which activates the AKT/PI3K pathway and is mainly responsible for the metabolic actions of insulin/IGF1) and GRB2 (which activates the ERK/MAPK pathway and primarily regulates cell growth and differentiation). Additionally, the INSR and IGF1R can phosphorylate other substrates, such as SHC and GAB1, which link multiple pathways. Together, these signals stimulate a variety of different downstream biological effects including mitogenesis, gene expression, glucose transport, and glycogen synthesis.