Alternative splicing, gene localization, and binding of SH2-B to the insulin receptor kinase domain

  title={Alternative splicing, gene localization, and binding of SH2-B to the insulin receptor kinase domain},
  author={Keats A. Nelms and Thomas J. O’Neill and Shiqing Li and Stevan R. Hubbard and Thomas A. Gustafson and William E. Paul},
  journal={Mammalian Genome},
Abstract. The SH2-B protein is an SH2-domain-containing molecule that interacts with a number of phosphorylated kinase and receptor molecules including the insulin receptor. Two isoforms of the SH2-B have been identified and have been proposed to arise through alternate splicing. Here we have identified a third isoform of the SH2-B protein, SH2-Bγ, that interacts specifically with the insulin receptor. This interaction required phosphorylation of residue Y1146 in the triple tyrosine motif… 

Kinase Activation through Dimerization by Human SH2-B

It is shown that the three alternatively spliced isoforms of human SH2-B readily homodimerize in yeast two-hybrid and cellular transfections assays, and this is mediated specifically by a unique domain in its amino terminus, providing direct mechanisms for activating and inhibiting JAK2 and other kinases from the inside of the cell.

Four PSM/SH2-B Alternative Splice Variants and Their Differential Roles in Mitogenesis*

These findings implicate differential roles of the PSM/SH2-B splice variants in specific mitogenic signaling pathways and predicts four distinctly sized protein products that have been demonstrated after cDNA expression.

Binding of SH2-B Family Members within a Potential Negative Regulatory Region Maintains JAK2 in an Active State

Together, the data suggest that SH2-Bβ and APS do not activate JAK2 as a consequence of their own dimerization, recruitment of an activator ofJAK2, or direct competition with a Jak2 inhibitor for binding to JAK3, rather they most likely induce or stabilize an active conformation of JAK1.

Disruption of the SH2-B Gene Causes Age-Dependent Insulin Resistance and Glucose Intolerance

The data suggest that SH2-B is a physiological enhancer of insulin receptor activation and is required for maintaining normal insulin sensitivity and glucose homeostasis during aging.

Phosphorylation of the Unique C-Terminal Tail of the Alpha Isoform of the Scaffold Protein SH2B1 Controls the Ability of SH2B1α To Enhance Nerve Growth Factor Function

The results suggest that the C-terminal tails of SH2B1 isoforms are key determinants of the cellular role of SH1B1, and the function of SH 2B1α is regulated by phosphorylation of the α tail.

Essential role of PSM/SH2‐B variants in insulin receptor catalytic activation and the resulting cellular responses

The results implicate an essential role of the PSM variants in the activation of the IR kinase and the resulting metabolic insulin response as well as internal IR ligands that in addition to potentiating the insulin response stimulate IR catalytic activation even in the absence of insulin.



Interaction between the Grb10 SH2 Domain and the Insulin Receptor Carboxyl Terminus (*)

The results suggest that Grb10 is a novel insulin receptor interactive protein and provide direct evidence for an insulin receptor substrate-1-independent function of the insulin receptor carboxyl terminus in protein binding.

Phosphotyrosine-dependent interaction of SHC and insulin receptor substrate 1 with the NPEY motif of the insulin receptor via a novel non-SH2 domain

It is concluded that SHC interacts directly with the IR and that phosphorylation of Tyr-960 within the IR juxtamembrane domain is necessary for efficient interaction.

Identification of SH2-Bbeta as a substrate of the tyrosine kinase JAK2 involved in growth hormone signaling

It is suggested that GH-induced activation and phosphorylation of JAK2 recruits SH2-Bbeta and its associated signaling molecules into a GHR-JAK2 complex, thereby initiating some as yet unidentified signal transduction pathways.

Expression, Characterization, and Crystallization of the Catalytic Core of the Human Insulin Receptor Protein-tyrosine Kinase Domain (*)

Biochemical characterization of the 35-kDa kinase revealed that the core kinase conserved the major functional properties of the native receptor kinase domain, making possible elucidation of its three-dimensional structure by x-ray crystallography.

PSM, an insulin-dependent, pro-rich, PH, SH2 domain containing partner of the insulin receptor.

Insulin stimulation results in a considerable spectrum of cellular responses, only part of which have been firmly correlated with the activation of established insulin receptor (IR) targets such as

Cloning and characterization of APS, an adaptor molecule containing PH and SH2 domains that is tyrosine phosphorylated upon B-cell receptor stimulation

Results indicate that APS, SH2-B and Lnk form a new adaptor family that links immune receptors to signaling pathways involved in tyrosine-phosphorylation, and plays a role in linkage from BCR to Shc/Grb2 pathway.

Specificity of the PTB Domain of Shc for β Turn-forming Pentapeptide Motifs Amino-terminal to Phosphotyrosine (*)

It is shown that the Shc PTB domain, but not the SH2 domain, binds with high affinity to phosphopeptides corresponding to the sequence surrounding Tyr250 of the polyoma virus middle T (mT) antigen (LLSNPTpYSVMRSK).

Grb10 Interacts Differentially with the Insulin Receptor, Insulin-like Growth Factor I Receptor, and Epidermal Growth Factor Receptor via the Grb10 Src Homology 2 (SH2) Domain and a Second Novel Domain Located between the Pleckstrin Homology and SH2 Domains*

The findings demonstrate the existence of a previously unidentified tyrosine kinase activity-dependent binding domain located between the Pleckstrin homology and SH2 domains of Grb10 and suggest that the presence of two distinct protein interaction domains may help to determine the specificity by which Grb 10 interacts with different receptors.

Interaction of the molecular weight 85K regulatory subunit of the phosphatidylinositol 3-kinase with the insulin receptor and the insulin-like growth factor-1 (IGF- I) receptor: comparative study using the yeast two-hybrid system.

It is found that the IR is more efficient in interacting with the p85 than is the IGF-IR, and mutations of the three major autophosphorylation sites indicate that interactions with p85 are dependent on the receptor tyrosine kinase activity.