scholarly journals Identification of SH2B2β as an Inhibitor for SH2B1- and SH2B2α-Promoted Janus Kinase-2 Activation and Insulin Signaling

Endocrinology ◽  
2007 ◽  
Vol 148 (4) ◽  
pp. 1615-1621 ◽  
Author(s):  
Minghua Li ◽  
Zhiqin Li ◽  
David L. Morris ◽  
Liangyou Rui
Keyword(s):  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Insulin Signaling ◽  
Sh2 Domain ◽  
Janus Kinase ◽  
Pleckstrin Homology Domain ◽  
Insulin Receptor Substrate ◽  
Janus Kinase 2 ◽  
Pleckstrin Homology ◽  
Insulin Receptor Substrate 1

The SH2B family has three members (SH2B1, SH2B2, and SH2B3) that contain conserved dimerization (DD), pleckstrin homology, and SH2 domains. The DD domain mediates the formation of homo- and heterodimers between members of the SH2B family. The SH2 domain of SH2B1 (previously named SH2-B) or SH2B2 (previously named APS) binds to phosphorylated tyrosines in a variety of tyrosine kinases, including Janus kinase-2 (JAK2) and the insulin receptor, thereby promoting the activation of JAK2 or the insulin receptor, respectively. JAK2 binds to various members of the cytokine receptor family, including receptors for GH and leptin, to mediate cytokine responses. In mice, SH2B1 regulates energy and glucose homeostasis by enhancing leptin and insulin sensitivity. In this work, we identify SH2B2β as a new isoform of SH2B2 (designated as SH2B2α) derived from the SH2B2 gene by alternative mRNA splicing. SH2B2β has a DD and pleckstrin homology domain but lacks a SH2 domain. SH2B2β bound to both SH2B1 and SH2B2α, as demonstrated by both the interaction of glutathione S-transferase-SH2B2β fusion protein with SH2B1 or SH2B2α in vitro and coimmunoprecipitation of SH2B2β with SH2B1 or SH2B2α in intact cells. SH2B2β markedly attenuated the ability of SH2B1 to promote JAK2 activation and subsequent tyrosine phosphorylation of insulin receptor substrate-1 by JAK2. SH2B2β also significantly inhibited SH2B1- or SH2B2α-promoted insulin signaling, including insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1. These data suggest that SH2B2β is an endogenous inhibitor of SH2B1 and/or SH2B2α, negatively regulating insulin signaling and/or JAK2-mediated cellular responses.

scholarly journals The Pleckstrin Homology Domain in Insulin Receptor Substrate-1 Sensitizes Insulin Signaling

1995 ◽  
Vol 270 (20) ◽  
pp. 11715-11718 ◽  
Author(s):  
Martin G. Myers ◽  
Timothy C. Grammer ◽  
Jennifer Brooks ◽  
Erin M. Glasheen ◽  
Ling-Mei Wang ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Insulin Signaling ◽  
Pleckstrin Homology Domain ◽  
Insulin Receptor Substrate ◽  
Pleckstrin Homology ◽  
Insulin Receptor Substrate 1

scholarly journals Regulation of Insulin Receptor Substrate 1 Pleckstrin Homology Domain by Protein Kinase C: Role of Serine 24 Phosphorylation

2006 ◽  
Vol 20 (8) ◽  
pp. 1838-1852 ◽  
Author(s):  
Ranmali Nawaratne ◽  
Alexander Gray ◽  
Christina H. Jørgensen ◽  
C. Peter Downes ◽  
Kenneth Siddle ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Insulin Receptor ◽  
Pleckstrin Homology Domain ◽  
Insulin Receptor Substrate ◽  
Pleckstrin Homology ◽  
Insulin Receptor Substrate 1 ◽  
Kinase C

scholarly journals Insulin stimulates the tyrosine dephosphorylation of docking protein p130cas (Crk-associated substrate), promoting the switch of the adaptor protein Crk from p130cas to newly phosphorylated insulin receptor substrate-1

1998 ◽  
Vol 334 (3) ◽  
pp. 595-600 ◽  
Author(s):  
Andrey SOROKIN ◽  
Eleanor REED
Keyword(s):  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Sh2 Domain ◽  
Stable Complex ◽  
Insulin Receptor Substrate ◽  
Dependent Manner ◽  
Insulin Receptor Substrate 1 ◽  
Docking Protein

The docking protein p130cas (Crk-associated substrate) forms a stable complex with the adaptor protein CrkII in a tyrosine-phosphorylation-dependent manner. Insulin-induced tyrosine phosphorylation of insulin receptor substrates results in the redistribution of CrkII between p130cas and insulin receptor substrate-1. A decrease in the association between CrkII and p130cas in response to insulin stimulation was detected in CHO cells stably expressing insulin receptor or insulin receptor substrate-1, and in L6 rat myoblasts. Along with the decrease in the association of CrkII with p130cas, the amount of tyrosine-phosphorylated insulin receptor substrate-1 co-precipitated with CrkII increased in all cell types studied. The insulin-induced decrease in the CrkII–p130cas association was further confirmed by Far Western Blot analysis with the Src homology 2 (SH2) domain of CrkII. Insulin regulates the association of CrkII with p130cas by tyrosine dephosphorylation of p130cas and co-ordinated tyrosine phosphorylation of insulin receptor substrate-1. Tyrosine-phosphorylated insulin receptor substrate-1 serves as a docking protein for multiple adaptor proteins and competes with p130cas for CrkII.

scholarly journals Dynamic Functional Relay between Insulin Receptor Substrate 1 and 2 in Hepatic Insulin Signaling during Fasting and Feeding

2008 ◽  
Vol 8 (1) ◽  
pp. 49-64 ◽  
Author(s):  
Naoto Kubota ◽  
Tetsuya Kubota ◽  
Shinsuke Itoh ◽  
Hiroki Kumagai ◽  
Hideki Kozono ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Insulin Signaling ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Hepatic Insulin Signaling

scholarly journals Serine Phosphorylation Proximal to Its Phosphotyrosine Binding Domain Inhibits Insulin Receptor Substrate 1 Function and Promotes Insulin Resistance

2004 ◽  
Vol 24 (21) ◽  
pp. 9668-9681 ◽  
Author(s):  
Yan-Fang Liu ◽  
Avia Herschkovitz ◽  
Sigalit Boura-Halfon ◽  
Denise Ronen ◽  
Keren Paz ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Insulin Treatment ◽  
Binding Domain ◽  
Serine Phosphorylation ◽  
Insulin Receptor Substrate ◽  
Control Mechanisms ◽  
Insulin Receptor Substrate 1 ◽  
Phosphotyrosine Binding Domain

ABSTRACT Ser/Thr phosphorylation of insulin receptor substrate (IRS) proteins negatively modulates insulin signaling. Therefore, the identification of serine sites whose phosphorylation inhibit IRS protein functions is of physiological importance. Here we mutated seven Ser sites located proximal to the phosphotyrosine binding domain of insulin receptor substrate 1 (IRS-1) (S265, S302, S325, S336, S358, S407, and S408) into Ala. When overexpressed in rat hepatoma Fao or CHO cells, the mutated IRS-1 protein in which the seven Ser sites were mutated to Ala (IRS-17A), unlike wild-type IRS-1 (IRS-1WT), maintained its Tyr-phosphorylated active conformation after prolonged insulin treatment or when the cells were challenged with inducers of insulin resistance prior to acute insulin treatment. This was due to the ability of IRS-17A to remain complexed with the insulin receptor (IR), unlike IRS-1WT, which underwent Ser phosphorylation, resulting in its dissociation from IR. Studies of truncated forms of IRS-1 revealed that the region between amino acids 365 to 430 is a main insulin-stimulated Ser phosphorylation domain. Indeed, IRS-1 mutated only at S408, which undergoes phosphorylation in vivo, partially maintained the properties of IRS-17A and conferred protection against selected inducers of insulin resistance. These findings suggest that S408 and additional Ser sites among the seven mutated Ser sites are targets for IRS-1 kinases that play a key negative regulatory role in IRS-1 function and insulin action. These sites presumably serve as points of convergence, where physiological feedback control mechanisms, which are triggered by insulin-stimulated IRS kinases, overlap with IRS kinases triggered by inducers of insulin resistance to terminate insulin signaling.

scholarly journals Tyrosine Phosphorylation of Insulin Receptor Substrate-1in VivoDepends upon the Presence of Its Pleckstrin Homology Region

1995 ◽  
Vol 270 (30) ◽  
pp. 18083-18087 ◽  
Author(s):  
Hedva Voliovitch ◽  
Daniel G. Schindler ◽  
Yaron R. Hadari ◽  
Simeon I. Taylor ◽  
Domenico Accili ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Insulin Receptor Substrate ◽  
Pleckstrin Homology ◽  
Homology Region
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