title: 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.
authors: Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Lili
authors: L
authors: Guo
authors: Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Diane L
authors: DL
authors: Costanzo-Garvey
authors: Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Deandra R
authors: DR
authors: Smith
authors: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Megan E
authors: ME
authors: Zavorka
authors: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Megan
authors: M
authors: Venable-Kang
authors: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Fred &Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Richard G
authors: RG
authors: MacDonald
authors: Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Fred &Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Robert E
authors: RE
authors: Lewis
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D049628:Body Size / Q000502:physiology; D015519:Bone Density / Q000502:physiology*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D050799:STAT5 Transcription Factor; C414620:fibroblast growth factor 21; C519530:insulin-like growth factor-1, mouse; D005346:Fibroblast Growth Factors; D007334:Insulin-Like Growth Factor I; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; C542241:KSR2 protein, mouse; D017346:Protein Serine-Threonine Kinases