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Insulin reverses growth hormone‐induced homologous desensitization
Author(s) -
Xu Jie,
Messina Joseph
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1079-b
Subject(s) - phosphorylation , mapk/erk pathway , stat5 , endocrinology , tyrosine phosphorylation , medicine , homologous desensitization , desensitization (medicine) , growth hormone receptor , insulin , signal transduction , insulin receptor , biology , janus kinase 2 , kinase , chemistry , microbiology and biotechnology , growth hormone , receptor , hormone , insulin resistance
Growth hormone (GH) is secreted in a pulsatile pattern to promote body growth and metabolism. GH exerts its function by activating several signaling pathways, including JAK2/STAT and MEK/ERK. Reactivation of STAT5 is required for GH‐induced male‐specific body growth and hepatic gene expression. ERK1/2 activation by GH plays important roles in gene expression, cell proliferation and growth. We previously reported that, in liver‐derived cells, repeated GH pulses induce STAT5 phosphorylation, but not ERK1/2 phosphorylation [Ji S, J Biol Chem 277:28384–28393 (2002)]. In the present study, we first investigated the mechanisms underlying GH‐induced homologous desensitization. A second GH pulse activated signaling upstream of MEK1/2, including JAK2, Ras, and Raf‐1, but not MEK1/2 and ERK1/2, suggesting disconnect between activation of Raf‐1 and MEK1/2. We then examined the effects of insulin on GH‐induced signaling desensitization. Insulin restored the ability of a second GH pulse to induce MEK/ERK phosphorylation, without altering GHR levels or activation of JAK2 and Raf‐1. Further investigation suggested that insulin restored tyrosine phosphorylation of Kinase Suppressor of Ras (KSR), a scaffolding protein for MEK1/2. Previous GH exposure also induced desensitization of STAT1 and STAT3, but this desensitization was not reversed by insulin. Our study suggests that insulin may act to specifically resensitize GH‐induced MEK/ERK signaling. This insulin‐regulated resensitization may be necessary for the full growth in response to GH. This work was supported by NIH Grants DK40456 and DK62071 (to J.L.M.).

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