IndraLab
Statements
rlimsp
"Here, we used a NIH 3T3 cell transformation system to underscore the critical involvement of signaling through Src, orchestrated by the Src phosphorylation site on EGFR (Y845), which appears crucial in linking mutant EGFRs to oncogenesis and constitutive activation of specific signaling pathways."
sparser
"It is well known that Src can phosphorylate EGFR on Y845, but it has been reported that Src phosphorylation on this residue does not affect EGFR autokinase activity [ xref ], suggesting that EGFR Y1173 phosphorylation should not be decreased by Src inhibition, unless the anti-Src agents have cross-reactivity with EGFR."
rlimsp
"In transient transfection assays, not only epidermal growth factor but also serum- and lysophosphatidic acid-induced DNA synthesis was ablated in a dominant-negative fashion by a Y845F mutant of the EGFR, indicating that c-Src-induced phosphorylation of Y845 is critical for the mitogenic response to both the EGFR and a G protein-coupled receptor (lysophosphatidic acid receptor)."
sparser
"In this study, we demonstrated that c-Src-dependent phosphorylation of tyrosine 845 (Tyr 845) on EGFR was required for DNA synthesis induced by the G protein-coupled agonists, endothelin (ET) and lysophosphatidic acid (LPA), and the cytokine, growth hormone (GH), in murine fibroblast and breast cancer model systems."
reach
"At the top of the ERBB signaling cascade, SRC phosphorylation of EGFR on residue Y845 in the catalytic domain stabilizes kinase activation, and on Y1101 in the C-terminal tail promotes EGFR binding to SHC [XREF_BIBR]; SRC also enhances EGFR activation of the JAK-STAT pathway [XREF_BIBR] (see Weimbs review)."
sparser
"For example, it has been described that phosphorylation of EGFR Tyr845 by c-Src, in an EGF-independent manner, can lead to the induction of macropinocytosis [31, 32], Src-kinase activity plays an important role during macropinosome formation and trafficking [48], and can synergistically enhance macropinocytic induction [49]."
rlimsp
"Mutation at tyrosine 869 (845) residue, an Src phosphorylation site, decreased the phosphorylation levels of wild-type EGFR and other mutants, but not that of S768I and L861Q mutants, suggesting that S768I and L861Q mutants became Src independent for their activation and biological functions."
reach
"In contrast, blockade or silencing of Src only suppressed EGF induced EGFR phosphorylation at Y845 but did not affect EGFR autophosphorylation at Y1068 by EGF, indicating that ligand dependent EGFR phosphorylation at Y845 depends on Src whereas autophosphorylation at other residues such as Y1068 is Src independent."
reach
"Later studies by Jung et al. [XREF_BIBR] showed that TM4SF5 is responsible for the recruitment of negatively regulated Src to the vicinity of EGFR, by which Src becomes activated and phosphorylates Y845 of EGFR, and cells acquire the ability to form invasive protrusions that involve actin and cortactin interactions."
rlimsp
"Inhibition of protein tyrosine phosphatase(s) by vanadate induces the activation of Src (Tyr-416 phosphorylation), which transactivates epidermal growth factor receptor (EGFR) indirectly through the shedding of heparin-binding (HB)-EGF, and directly via the Src-catalyzed phosphorylation of EGFR at Tyr-845."
rlimsp
"The Src phosphorylation site on EGFR, Y845, is important for constitutive activation of mutant EGF receptors (A) Cells expressing the indicated EGFRs were serum-deprived for 3 hr and then either left unstimulated (−) or stimulated (+) with 10 ng/ml EGF for 10 min., or (B) Cells were placed in media with 10 % FBS (Normal Growth Condition) or 0.1 % FBS for 3 hr (3 hr serum-deprivation)."
rlimsp
"First, c-Src phosphorylates Y845 of the EGFR, a residue that resides in the activation loop of the kinase domain and is highly conserved among receptor tyrosine kinases (Biscardi et al 1999a)(Hunter and Cooper 1985). (Note that several reports indicate that Src-independent phosphorylation of Y845 can occur of (Qiu et al 2009)(Yang et al 2008))."
rlimsp
"Pretreatment of MDA-MB-468 cells with the Src inhibitor dasatinib decreased the degree of EGFR phosphorylation on the Src phosphorylation site Tyr845, but did not alter the amount of EGFR that co-immunoprecipitated with CDCP1 (Fig. 2f). Pretreatment of the cells with the EGFR/HER2 inhibitor lapatinib reduced the amount of EGFR that co-immunoprecipitated with CDCP1. Similar results were evident in the presence or absence of cell pretreatment with EGF. Overall, the data in Fig. 2a–f suggest the possibility that CDCP1/EGFR/Src ternary complexes may facilitate CDCP1 and EGFR tyrosine phosphorylation by CDCP1-associated Src. To provide support for this model, CDCP1-containing complexes were immunoprecipitated from MDA-MB-468 cells, eluted with FLAG peptide and the immunoprecipitates split into separate aliquots and subjected to in vitro kinase assays performed in the presence or absence of ATP, the Src inhibitor dasatinib, or the EGFR/HER2 inhibitor lapatinib. CDCP1-associated Src became phosphorylated on activation loop site Tyr416; activated Src, and phosphorylated EGFR on the transactivation site Tyr845 because both events were blocked by dasatinib, but unaffected by lapatinib (Fig. 2g)."
reach
"Since we observed phosphorylation of EGFR on tyrosine 845 in response to treatment with PGE 2, we next examined the possible contribution of Src, which is known to phosphorylate EGFR at tyrosine 845 and previously shown to transactivate EGFR in response to PGE 2 in colorectal cancer cells."
rlimsp
"For the past eighteen years or so, since the initial discovery of the Src phosphorylation of EGFR on Y845, much progress has been made in the recognition that Y845 phosphorylation takes place in a variety of cancerous and normal physiological cell contexts, as well as in the understanding that Y845 phosphorylation plays pivotal roles in these cellular contexts (Figure 2)."
rlimsp
"Furthermore, we found that treating VSMCs with OVA stimulated the phosphorylation of EGFR at Tyr-845. The Src-catalyzed phosphorylation of EGFR at this residue is thought to be essential for mitogenic signaling by EGFR, as cells expressing Y845F mutant of EGFR showed markedly decreased DNA synthesis in response to EGF (Tice et al. 1999)."
sparser
"Phosphorylation of Y845 of EGFR by SRC stimulates the mitochondrial trafficking of EGFR. xref Mitochondrial EGFR associates with and phosphorylates a subunit of Complex IV, cytochrome oxidase subunit II (COXII) at the inner mitochondrial membrane, leading to decrease in COXII activity and respiratory inhibition. xref "
sparser
"It was reported that the signal transducer and activator of trans cription 5b (STAT5b), c-Src and EGFR play integral roles in estrogen-stimulated proliferation of ER-positive breast cancer cells ( xref ); estrogen-induced Src activation and Src-dependent phosphorylation of EGFR-Y845 recruit STAT5 as a downstream effector of phosphorylated EGFR-Y845."
rlimsp
"It is well known that Src can phosphorylate EGFR on Y845, but it has been reported that Src phosphorylation on this residue does not affect EGFR autokinase activity [13], suggesting that EGFR Y1173 phosphorylation should not be decreased by Src inhibition, unless the anti-Src agents have cross-reactivity with EGFR."
reach
"In addition, we investigated whether EGFR activation by diesel exposure could be mediated by Src activation and phosphorylation of Src Tyr 416 and leading to transactivation of EGFR at Tyr 845 and whether activation of EGFR would increase the downstream MEK-ERK pathway signalling, linked to proliferation and differentiation."
reach
"It is well known that Src can phosphorylate EGFR on Y845, but it has been reported that Src phosphorylation on this residue does not affect EGFR autokinase activity [XREF_BIBR], suggesting that EGFR Y1173 phosphorylation should not be decreased by Src inhibition, unless the anti-Src agents have cross-reactivity with EGFR."
sparser
"Search of the physiological roles played by these two overexpressed PTKs has demonstrated a breakthrough finding that they exert synergism in promoting as well as maintaining cancerous cell growth, the main phenomenon implicated in which is Y845 phosphorylation of EGFR by Src [ xref ]."
sparser
"In PC3 cells binding of neurotensin to Neurotensin receptors (NTRs), which are members of GPCR family, induces c-Src-dependent EGFR phosphorylation at Y845 [ xref ], and several GPCR agonists induce rapid and transient activation of Src-family members in a variety of cell types ( xref ) [ xref ]."
rlimsp
"At this time, however, phosphorylation of Y845 by Src was unknown. Later, Wasilenko et al. [39] made the first demonstration that Src is capable of phosphorylating EGFR on unknown tyrosine residue(s). In this work, trypsin-digested phosphopeptides were analyzed in cells expressing both EGFR and Src, and thus the identification of phosphorylated Y845 was not made. The first evidence showing that Src directly phosphorylates EGFR on Y845 was provided by our work [19], where in vitro phosphorylated EGFR in the presence of Src was analyzed by tryptic digestion and two-dimensional electrophoresis, by which the identities of EGFR-derived phosphopeptides and a synthetic peptide containing phosphorylated Y845 were evaluated."
reach
"The first evidence showing that Src directly phosphorylates EGFR on Y845 was provided by our work [XREF_BIBR], where in vitro phosphorylated EGFR in the presence of Src was analyzed by tryptic digestion and two-dimensional electrophoresis, by which the identities of EGFR derived phosphopeptides and a synthetic peptide containing phosphorylated Y845 were evaluated."
rlimsp
"Epidermal growth factor receptor translocation to the mitochondria: regulation and effect. Co-overexpression of the epidermal growth factor (EGF) receptor (EGFR) and c-Src frequently occurs in human tumors and is linked to enhanced tumor growth. In experimental systems this synergistic growth requires EGF-dependent association of c-Src with the EGFR and phosphorylation of Tyr-845 of the receptor by c-Src."
sparser
"For the past eighteen years or so, since the initial discovery of the Src phosphorylation of EGFR on Y845, much progress has been made in the recognition that Y845 phosphorylation takes place in a variety of cancerous and normal physiological cell contexts, as well as in the understanding that Y845 phosphorylation plays pivotal roles in these cellular contexts ( xref )."
rlimsp
"The first evidence showing that Src directly phosphorylates EGFR on Y845 was provided by our work [19], where in vitro phosphorylated EGFR in the presence of Src was analyzed by tryptic digestion and two-dimensional electrophoresis, by which the identities of EGFR-derived phosphopeptides and a synthetic peptide containing phosphorylated Y845 were evaluated."
reach
"For the past eighteen years or so, since the initial discovery of the Src phosphorylation of EGFR on Y845, much progress has been made in the recognition that Y845 phosphorylation takes place in a variety of cancerous and normal physiological cell contexts, as well as in the understanding that Y845 phosphorylation plays pivotal roles in these cellular contexts (XREF_FIG)."
reach
"For example, it has been described that phosphorylation of EGFR Tyr845 by c-Src, in an EGF-independent manner, can lead to the induction of macropinocytosis [31, 32], Src-kinase activity plays an important role during macropinosome formation and trafficking [48], and can synergistically enhance macropinocytic induction [49]."
rlimsp
"B: EGFR Tyr-845 phosphorylation (Src phosphorylation site) and total EGFR levels in MC treated with or without the Src inhibitors, 2 μmol/L PP2 or 2.5 μmol/L SU6656 (SU), for the final 24 h. C: EGFR Tyr-1173 phosphorylation (autophosphorylation site) and total EGFR levels in cells treated with or without 2 μmol/L PP2 for 24 h. D: EGFR Tyr-845 phosphorylation (Src phosphorylation site) and total EGFR levels in cells treated with the EGFR kinase inhibitor, 200 nmol/L AG1478 (AG), for 48 h. E: EGFR pTyr-845 and pTyr-1173 and total EGFR immunoblots in cells grown in the presence or absence of 100 μmol/L TAPI-2 for 48 h. Results from four to six independent experiments are quantified in the graphs."