Differential Activation of Epidermal Growth Factor (EGF) Receptor Downstream Signaling Pathways by Betacellulin and EGF

Saito, Tsugumichi; Okada, Shuichi; Ohshima, Kihachi; Yamada, Eijiro; Sato, Minoru; Uehara, Yutaka; Shimizu, Hiroyuki; Pessin, Jeffrey E.; Mori, Masatomo

doi:10.1210/en.2004-0401

Cited by 82 publications

(57 citation statements)

References 40 publications

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“…This difference in efficacy may reflect differences in the pattern of receptor or adapter protein phosphorylation generated by two ligands binding to the same receptor. Analogous results have been reported for the epidermal growth factor (EGF) receptor, ErbB1, where binding of EGF and betacellulin generate similar levels of ErbB1 Y1086 phosphorylation, but betacellulin produces greater Akt activation and a more robust anti-apoptotic response than EGF (47,48). Alternatively, the reduced IGF-2 FIGURE 7.…”

Section: Discussionsupporting

confidence: 71%

The Insulin-like Growth Factor Type 1 and Insulin-like Growth Factor Type 2/Mannose-6-phosphate Receptors Independently Regulate ERK1/2 Activity in HEK293 Cells

El‐Shewy

Lee

Obeid

et al. 2007

Journal of Biological Chemistry

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Insulin-like growth factor types 1 and 2 (IGF-1; IGF-2) and insulin-like peptides are all members of the insulin superfamily of peptide hormones but bind to several distinct classes of membrane receptor. Like the insulin receptor, the IGF-1 receptor is a heterotetrameric receptor tyrosine kinase, whereas the IGF-2/ mannose 6-phosphate receptor is a single transmembrane domain protein that is thought to function primarily as clearance receptors. We recently reported that IGF-1 and IGF-2 stimulate the ERK1/2 cascade by triggering sphingosine kinasedependent "transactivation" of G protein-coupled sphingosine-1-phosphate receptors. To determine which IGF receptors mediate this effect, we tested seven insulin family peptides, IGF-1, IGF-2, insulin, and insulin-like peptides 3, 4, 6, and 7, for the ability to activate ERK1/2 in HEK293 cells. Only IGF-1 and IGF-2 potently activated ERK1/2. Although IGF-2 was predictably less potent than IGF-1 in activating the IGF-1 receptor, they were equipotent stimulators of ERK1/2. Knockdown of IGF-1 receptor expression by RNA interference reduced the IGF-1 response to a greater extent than the IGF-2 response, suggesting that IGF-2 did not signal exclusively via the IGF-1 receptor. In contrast, IGF-2 receptor knockdown markedly reduced IGF-2-stimulated ERK1/2 phosphorylation, with no effect on the IGF-1 response. As observed previously, both the IGF-1 and the IGF-2 responses were sensitive to pertussis toxin and the sphingosine kinase inhibitor, dimethylsphingosine. These data indicate that endogenous IGF-1 and IGF-2 receptors can independently initiate ERK1/2 signaling and point to a potential physiologic role for IGF-2 receptors in the cellular response to IGF-2.The insulin superfamily family of peptide hormones, consisting of insulin, insulin-like growth factor type 1 (IGF-1), 2 insu- Although all members of the insulin superfamily share structural homology, their signals are transmitted through binding to a number of structurally dissimilar receptors. IGF-1 and IGF-2 are single chain polypeptides, with sequences 62% identical to that of proinsulin. Both contain a short D domain that is not present in insulin, and unlike insulin, they do not undergo post-translational proteolysis, such that the A and B domains remain linked in the mature peptide by a C domain analogous to the C peptide of insulin (1, 2). IGF-1 and IGF-2 bind two structurally distinct types of receptor, referred to as the IGF-1 and IGF-2/mannose-6-phosphate (M6P) receptors. The IGF-1 receptor is heterotetrameric transmembrane receptor tyrosine kinase that is structurally and functionally related to the insulin receptor. It is composed of two extracellular ␣-subunits that contain the ligand-binding domain and two transmembrane ␤-subunits that possess intrinsic ligand-stimulated tyrosine kinase activity (3,4). Ligand binding to the ␣-subunit activates the ␤-subunit tyrosine kinase, resulting in tyrosine phosphorylation of intracellular adapter proteins, such as insulin receptor substrate (IRS)-1 and IRS-2, Shc, and...

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Section: Discussionsupporting

confidence: 71%

The Insulin-like Growth Factor Type 1 and Insulin-like Growth Factor Type 2/Mannose-6-phosphate Receptors Independently Regulate ERK1/2 Activity in HEK293 Cells

El‐Shewy

Lee

Obeid

et al. 2007

Journal of Biological Chemistry

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“…It has been shown that specific EGFR downstream signaling pathways can be elicited by phosphorylation on specific sites. For example, the phosphorylation of Y1068 can recruit GAB-1 or growth factor receptor-bound protein 2 (Grb-2) to activate survival signals (40), whereas the phosphorylation of Y1173 is responsible for eliciting the activation of ERK via inhibition of the SH2 domain-containing transforming protein (SHC) and Grb2 (41,42). Furthermore, the up-regulation of pY1173 also has been reported in patients who have NSCLC with EGFR mutation, and Akt, MAPK, and Stat3 signaling is higher in pY1173-positive patients (43).…”

Section: Discussionmentioning

confidence: 99%

Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition

Yen

Liu²,

Chen³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

101

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Epidermal growth factor receptor (EGFR) is a heavily glycosylated transmembrane receptor tyrosine kinase. Upon EGF-binding, EGFR undergoes conformational changes to dimerize, resulting in kinase activation and autophosphorylation and downstream signaling. Tyrosine kinase inhibitors (TKIs) have been used to treat lung cancer by inhibiting EGFR phosphorylation. Previously, we demonstrated that EGFR sialylation suppresses its dimerization and phosphorylation. In this report, we further investigated the effect of sialylation on the phosphorylation profile of EGFR in TKIsensitive and TKI-resistant cells. Sialylation was induced in cancer progression to inhibit the association of EGFR with EGF and the subsequent autophosphorylation. In the absence of EGF the TKIresistant EGFR mutant (L858R/T790M) had a higher degree of sialylation and phosphorylation at Y1068, Y1086, and Y1173 than the TKI-sensitive EGFR. In addition, although sialylation in the TKIresistant mutants suppresses EGFR tyrosine phosphorylation, with the most significant effect on the Y1173 site, the sialylation effect is not strong enough to stop cancer progression by inhibiting the phosphorylation of these three sites. These findings were supported further by the observation that the L858R/T790M EGFR mutant, when treated with sialidase or sialyltransferase inhibitor, showed an increase in tyrosine phosphorylation, and the sensitivity of the corresponding resistant lung cancer cells to gefitinib was reduced by desialylation and was enhanced by sialylation.E pidermal growth factor receptor (EGFR), one of the most studied receptor tyrosine kinases, is a drug target for cancer therapy, because its kinase activity correlates with tumorigenicity (1). Under normal conditions, EGFR forms dimers upon ligand binding and induces kinase activation (2-6). The conformational change of EGFR from tethered to extended form induced by ligand binding involves the exposure of the interface, followed by dimerization, activation, and autophosphorylation (7). The phosphorylation code of EGFR determines the propensity of the downstream signaling network to regulate cell proliferation, survival, migration, and angiogenesis (8, 9).In a significant fraction of patients with nonsmall cell lung cancer (NSCLC), especially patients in Asia and those with the adenocarcinoma subtype, mutations in the kinase domain of EGFR cause constitutive activation and have been identified as an important factor in EGFR dysregulation (10, 11). Particularly, mutation from leucine to arginine at position 858 (L858R) and, less significantly, deletion of exon 19 that eliminates four amino acids (LREA) account for ∼90% of the mutations involved in the constitutive activation of EGFR. These mutations are commonly found in patients with increased sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib (12-14). However, most patients with such mutations show resistance within months after TKI therapy, and >50% of them develop a second EGFR mutation, T790M, which confers TKI resi...

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“…The α v integrin subunit induced the phosphorylation of 845, 1068845, , 1086845, , and 1173845, (Moro et al, 2002. In addition, ionizing radiation induced phosphorylation of 992 and 1173 while betacellulin induced 1068 (Sturla et al, 2005;Saito et al, 2004). While these are major sites of phosphorylation in response to EGF, it is interesting that differential phosphorylation occurs in response to specific biologic activation.…”

Section: Discussionmentioning

confidence: 99%

Injury and nucleotides induce phosphorylation of epidermal growth factor receptor: MMP and HB-EGF dependent pathway

Boucher

Yang

Mayo

et al. 2007

Experimental Eye Research

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The early events that occur rapidly after injury trigger signal cascades that are essential for proper wound closure of corneal epithelial cells. We hypothesize that injury releases ATP, which stimulates purinergic receptors and elicits the phosphorylation of epidermal growth factor receptor (EGFR) tyrosine residues and subsequent cell migration by a MMP and HB-EGF dependent pathway. We demonstrated that the inhibition of purinergic receptors with the antagonist, Reactive Blue 2, abrogated the phosphorylation of EGFR and ERK. Preincubation of cells with the EGFR kinase inhibitor, AG1478, and subsequent stimulation by injury or ATP resulted in a decrease in phosphorylation of EGFR and migration. Furthermore, downregulation of EGFR by siRNA, inhibited the EGF induced intracellular Ca 2+ wave. However, the response to injury and ATP was retained indicating the presence of 2 signaling pathways. Inhibition with either CRM197 or TIMP-3 decreased injury and nucleotide induced phosphorylation of both EGFR and ERK. Incubation in the presence of a functional blocking antibody to HB-EGF also resulted in a decrease in the phosphorylation of EGFR. In addition, cell migration was inhibited by CRM197 and rescued when cells were incubated with HB-EGF. We showed that injury induced phosphorylation of specific tyrosine residues and found that a similar pattern of phosphorylation was induced by trinucleotides. These studies indicate that injury induced purinergic receptor activation leads to phosphorylation of EGFR, ERK and migration.

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Differential Activation of Epidermal Growth Factor (EGF) Receptor Downstream Signaling Pathways by Betacellulin and EGF

Cited by 82 publications

References 40 publications

The Insulin-like Growth Factor Type 1 and Insulin-like Growth Factor Type 2/Mannose-6-phosphate Receptors Independently Regulate ERK1/2 Activity in HEK293 Cells

The Insulin-like Growth Factor Type 1 and Insulin-like Growth Factor Type 2/Mannose-6-phosphate Receptors Independently Regulate ERK1/2 Activity in HEK293 Cells

Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition

Injury and nucleotides induce phosphorylation of epidermal growth factor receptor: MMP and HB-EGF dependent pathway

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