Cell non-autonomous regulation of hepatic IGF-1 and neonatal growth by Kinase Suppressor of Ras 2 (KSR2)

Abstract

Individuals with poor postnatal growth are at risk for cardiovascular and metabolic problems as adults. Here we show that disruption of the molecular scaffold Kinase Suppressor of Ras 2 (KSR2) causes selective inhibition of hepatic GH signaling in neonatal mice with impaired expression of IGF-1 and IGFBP3. ksr2−/− mice are normal size at birth but show a marked increase in FGF21 accompanied by reduced body mass, shortened body length, and reduced bone mineral density (BMD) and content (BMC) first evident during postnatal development. However, disrupting FGF21 in ksr2−/− mice does not normalize mass, length, or bone density and content in fgf21−/−ksr2−/− mice. Body length, BMC and BMD, but not body mass, are rescued by infection of two-day-old ksr2−/− mice with a recombinant adenovirus encoding human IGF-1. Relative to wild-type mice, GH injections reveal a significant reduction in JAK2 and STAT5 phosphorylation in liver, but not in skeletal muscle, of ksr2−/− mice. However, primary hepatocytes isolated from ksr2−/− mice show no reduction in GH-stimulated STAT5 phosphorylation. These data indicate that KSR2 functions in a cell non-autonomous fashion to regulate GH-stimulated IGF-1 expression in the liver of neonatal mice, which plays a key role in the development of body length.

Coordinating ERK signaling via the molecular scaffold Kinase Suppressor of Ras

“…In contrast to the mild phenotype of ksr1 –/– mice, ksr2 –/– mice have reduced fertility and become spontaneously obese 56 – 59 . Pathways regulating adaptive thermogenesis, metabolic rate, and leptin-sensitive food consumption are implicated in KSR2-dependent energy balance 56 – 60 .…”

Cyp1b1 directs Srebp-mediated cholesterol and retinoid synthesis in perinatal liver; Association with retinoic acid activity during fetal development

“…The low presence of Lrat and retinyl esters and enrichment of activated stellate markers suggests an altered basal state that may be more sensitive to these changes [14]. Postnatal increases in Igf1 expression [98] parallel the major increases in hepatocyte gene expression, including the 15 percent that depend on Cyp1b1 and retinol, which Pathways that convert acetate to cholesterol or oleoyl-CoA and retinaldehyde to RA or retinyl esters. All processes are inhibited in Cyp1b1-/-pups (KO) ( Table 1).…”

RETRACTED ARTICLE: K-Ras G12V/Y40C -PI3K/AKT pathway regulates H1.4 S35ph through PKA to promote the occurrence and development of osteosarcoma cancer

“…Ras-PI3K/AKT pathway was complex regulation progress which can regulate several downstream factors [21]. In order to investigate more about the underlying mechanism about how Ras pathway achieved their functions, we explored several downstream factors CYR61 [22], IGFBP3 [23], WNT16B [24], NT5E [25], GDF15 [26], CARD16 [27], which participated tumor cell growth and metastasis. Then, we observed that Ras G12V/Y40C pathway up-regulated the expression of CYR61 (p<.01), IGFBP3 (p<.01), WNT16B (p<.01) and decreased the expression of NT5E (p<.01), GDF15 (p<.001), GARD16 (p<.01, Figure 3(A)).…”