Tyrosine Phosphatase SHP2 Positively Regulates GH Signaling

In contrast to these data pointing to a negative regulatory role for SHP-1 in GH signaling, a related SH2 domain-containing tyrosine phosphatase, termed SHP-2, appears to exert positive effects on GH signaling. GH treatment of cultured preadipocytes leads to tyrosine phosphorylation of SHP-2 and the association of SHP-2 with the adaptor molecule Grb2 and with a transmembrane glycoprotein known as SIRPa. SIRPa and the closely related protein SHPS-1 interact via their intracellular phosphotyrosine residues with the SH2 domains of SHP-2, and in some cases SHP-1, and serve as substrates for the SHPs' tyrosine phosphatase activity. In the case of EGF and insulin signaling, SIRPs exert a negative role that is dependent on SIRP tyrosine phosphorylation. While SIRPs can apparently be tyrosine phosphorylated by JAK2 in response to GH, their role (positive or negative, direct or indirect) in GH signaling is uncertain.

One possibility is that SHP-2 positively regulates GH signaling leading to c-fos activation by augmenting activation of the Ras-Raf-MAP kinase (ERK) pathway. This is suggested by the correlation of GH-induced SHP-2 tyrosine phosphorylation with SHP-2's ability to associate with Grb2, and by the finding that overexpression of a catalytically-inactive SHP-

2 mutant protein specifically inhibits GH-induced trans-activation of a c-/os-reporter gene construct. The mechanism for this positive effect of SHP-2, and whether SIRP is required for this effect, are important

Fig. 13. SOCS/CIS protein inhibition of GH-induced JAK-STAT signaling. SOCS/CIS proteins (general structure shown at top) are synthesized as early response gene products following GH stimulation and are proposed to inhibit further signaling by binding to phosphotyrosine residues on GHR, as shown here for CIS, and/or JAK2, as shown for SOCS. SOCS/CIS protein binding may in turn facilitate ubiquitination and degradation of the receptor-JAK-SOCS/CIS complex, as described in the text. (Based in part on Ram PA, Waxman DJ. J Biol Chem; 1999, 274:35553-35561.)

Fig. 13. SOCS/CIS protein inhibition of GH-induced JAK-STAT signaling. SOCS/CIS proteins (general structure shown at top) are synthesized as early response gene products following GH stimulation and are proposed to inhibit further signaling by binding to phosphotyrosine residues on GHR, as shown here for CIS, and/or JAK2, as shown for SOCS. SOCS/CIS protein binding may in turn facilitate ubiquitination and degradation of the receptor-JAK-SOCS/CIS complex, as described in the text. (Based in part on Ram PA, Waxman DJ. J Biol Chem; 1999, 274:35553-35561.)

open questions. Given that the tyrosine phosphatase activity of SHP-2 is required for it to augment this GH signal, it seems likely that dephosphorylation of particular cellular substrates, possibly including SIRP, may underly this action of SHP-2. By contrast, other studies show that SHP-2 can bind to JAK2 kinase in a reaction that does not require SHP-2's SH2 domains or its tyrosine phosphatase activity, but does not lead to JAK2 dephosphorylation.

Delicious Diabetic Recipes

Delicious Diabetic Recipes

This brilliant guide will teach you how to cook all those delicious recipes for people who have diabetes.

Get My Free Ebook


Post a comment