Meta-Biol

• Pathways

GH has short term effects that mimic the actions of insulin in tissues that have been deprived of GH, including increased amino acid transport, glucose transport, and lipogenesis (Davidson 1987). GH and insulin have overlapping signaling pathways (Dominici et al. 2005). GH stimulates tyrosyl phosphorylation of insulin receptor substrate-1 (IRS-1) (Souza et al. 1994, Thirone et al. 1999), and IRS-2 (Argetsinger et al. 1996, Thirone et al. 1999), although more modestly than insulin or IGF-1. Tyrosyl phosphorylation of IRS-1 and IRS-2 in response to insulin provides binding sites for specific proteins containing SH2 domains, including the 85-kDa regulatory subunit of phosphatidylinositol 3-kinase (PI3K), tyrosine phosphatase SHP2, and Grb2. This is one of several mechanisms proposed to explain the stimulatory effect of GH on the PI3-kinase/Akt pathway (Jin et al. 2008). GH promotes the binding of the 85-kDa regulatory subunit of PI3K to IRS-1 and IRS-2 in cultured cells (Ridderstrale et al. 1995, Argetsinger et al. 1995, 1996). Studies using truncated or mutated GHRs suggest that tyrosyl phosphorylation of IRS-1, IRS-2, and Shc is dependent on JAK2 activation (Argetsinger et al. 1995, 1996, VanderKuur et al. 1995). Despite a strong correlation between JAK2 activation and IRS phosphorylation it is not clear whether there is a direct association. JAK2 has been reported to interact directly with IRS in response to angiotensin II (Velloso et al. 1996) but also reported to interact indirectly via SH2B in response to leptin (Duan et al.2004).