Insulin-EGF receptor chimerae mediate tyrosine transphosphorylation and serine/threonine phosphorylation of kinase-deficient EGF receptors

Tartare, S; Ballotti, Robert; Lammers, Reiner; Alengrin, F; Dull, Thomas J.; Schlessinger, Joseph; Ullrich, Axel; Obberghen, E. Van

doi:10.1016/s0021-9258(18)92903-0

Cited by 16 publications

(14 citation statements)

References 39 publications

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“…The control construct MF pk 3E had no effect on MAP kinase activity either in the presence or in the absence of FK1012. These results demonstrate that dimerization or oligomerization of the β subunits of the insulin receptor is sufficient to activate insulin receptor signaling, consistent with previous studies on other chimeric insulin receptors [33,34]. The recruitment of Src homology 2 (SH2) domain-containing cytoplasmic proteins such as the p85 subunit of phosphoinositide 3′ kinase, Shc, Grb2, and phospholipase Cγ [35] to the membrane-inserted, phosphorylated -activated -receptor is believed to be a critical step in RTK signal transduction.…”

Section: Resultssupporting

confidence: 89%

Small-molecule control of insulin and PDGF receptor signaling and the role of membrane attachment

et al. 1998

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We have developed an approach using the small molecule FK1012 to conditionally activate chimeric proteins containing FKBP fused to the insulin receptor or to the PDGF beta receptor. Using this system, we were able to induce mesoderm formation in Xenopus animal-cap tissue and to demonstrate that membrane localization is required for RTK signaling in transfected cells. This system should allow the further dissection of RTK-mediated pathways.

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Section: Resultssupporting

confidence: 89%

Small-molecule control of insulin and PDGF receptor signaling and the role of membrane attachment

et al. 1998

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“…situated in trans [28]. Note that intermolecular phosphorylation appears to be the rule, since it has been found for all the tyrosine kinase receptors examined so far [7,29,30]. Concerning the biological implications of such an intermolecular transphosphorylation/transactivation model involving insulin receptors we have suggested that it could underlie the phenomenon of spare receptors seen in insulin action [27].…”

Section: Activation Of the Insulin Receptormentioning

confidence: 73%

Signalling through the insulin receptor and the insulin-like growth factor-I receptor

Obberghen

1994

Diabetologia

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The insulin receptor and the insulin-like growth factor I receptor belong to the family of tyrosine kinase receptors. Both receptors appear as a disulphide-linked dimer; each half of the dimer consisting of a 130 k M(r) alpha-subunit linked to a 90 k M(r) beta-subunit. Both halves of the dimer are linked together by disulphide bonds to form an alpha 2 beta 2 structure. The insulin receptor functions as an allosteric enzyme in which the binding of the hormone to the alpha-subunit leads to a series of conformational changes resulting in activation of the beta-subunit tyrosine kinase. Upon multisite autophosphorylation the latter becomes competent to phosphorylate cellular substrates resulting in the biological responses of insulin. Recent findings have recognized the mitogen activated protein kinase cascade as a central signalling circuitry linking cell surface receptors, such as the insulin receptor, to the nucleus, and playing a role in regulation of metabolism, growth and differentiation.

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“…This implies that IER activates one or several serine/ threonine kinases, which in turn phosphorylates the unoccupied HER K721A. Those observations demonstrate the existence ofcross-talk between an unoccupied EGF receptor and a ligand-activated EGF receptor kinase (37) .…”

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confidence: 67%

“…In a previous report, using a cell line expressing both a chimeric insulin-EGF tyrosine kinase receptor (IER) and a kinase-deficient EGF receptor (HER K72 IA), we have shown that the insulin-activated IER chimeric receptor phosphorylates the HER K721A on tyrosine residues (37). In addition to this tyrosine transphosphorylation, insulin enhances the phosphorylation of HER K721A on serine/threonine residues.…”

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confidence: 93%

Activation of insulin-epidermal growth factor (EGF) receptor chimerae regulates EGF receptor binding affinity.

Tartare

Ballotti

Lammers

et al. 1992

The Journal of Cell Biology

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. Cell surface tyrosine kinase receptors are subject to a rapid activation by their ligand, which is followed by secondary regulatory processes . The IHE2 cell line is a unique model system to study the regulation of EGF binding to EGF receptors after activation of the EGF receptor kinase. IHE2 cells express both a chimeric insulin-EGF receptor kinase (IER) and a kinase-deficient EGF receptor (HER K721A) . We have previously reported that IER is an insulin-responsive EGF receptor tyrosine kinase that activates one or several serine/threonine kinases, which in turn phosphorylate(s) the unoccupied HER K721A . In this article we show that insulin through IER activation induces a decrease in 'ZSI-EGF binding to IHE2 cells . Scatchard analysis indicates that, as for TPA, the effect of insulin can be accounted for by a loss of the high affinity bind-HE EGF receptor is a 170-kD transmembrane glycoprotein. The extracellular region contains the growth factor binding domain, whereas the intracellular re gion carries the tyrosine kinase catalytic domain (33,38) . These two functions of the EGF receptor, i .e., EGF binding and tyrosine kinase activity, play cardinal roles in the induction of the EGF biological effects and are subject to fine regulatory mechanisms. Receptor tyrosine kinase activity is positively regulated by EGF binding, which leads to tyrosine phosphorylation of the receptor (15,20,21,28) and of cellular substrates (38) . Recent data have indicated that tyrosine phosphorylation of the carboxy-terminal tail of the EGF receptor promotes the interaction with signaling molecules such as phospholipase C-.y and GTP-ase activating protein (GAP) ' (29) . In addition to these positive regulations, both the binding function and the kinase activity of the EGF receptor are subject to negative controls, which are mainly mediated by activation of protein kinase C. Thus, activators of protein kinase C, such as tetradecanoyl phorbol acetate (TPA) or PDGF, decrease the intrinsic tyrosine kinase ac- ing of EGF to HER K721A. Since this receptor transmodulation persists in protein kinase C downregulated IHE2 cells, it is likely to be due to a mechanism independent of protein kinase C activation. Using an in vitro system of 121 I-EGF binding to transmodulated IHE2 membranes, we illustrate that the inhibition of EGF binding induced by IER activation is related to the phosphorylation state of HER K721A. Further, studies with phosphatase 2A, or at a temperature (4°C) where only IER is functional, strongly suggest that the loss of high affinity EGF binding is related to the serine/ threonine phosphorylation of HER K721A after IER activation . Our results provide evidence for a "homologous desensitization" of EGF receptor binding after activation of the EGF receptor kinase of the IER receptor. tivity of the EGF receptor (7,16,17,23) . The major EGF receptor site phosphorylated by protein kinase C appears to be threonine 654 (12,22) . Studies using site-directed mutagenesis have shown that phosphorylation of the EGF recepto...

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Insulin-EGF receptor chimerae mediate tyrosine transphosphorylation and serine/threonine phosphorylation of kinase-deficient EGF receptors

Cited by 16 publications

References 39 publications

Small-molecule control of insulin and PDGF receptor signaling and the role of membrane attachment

Small-molecule control of insulin and PDGF receptor signaling and the role of membrane attachment

Signalling through the insulin receptor and the insulin-like growth factor-I receptor

Activation of insulin-epidermal growth factor (EGF) receptor chimerae regulates EGF receptor binding affinity.

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