Src and Pyk2 Mediate G-protein-coupled Receptor Activation of Epidermal Growth Factor Receptor (EGFR) but Are Not Required for Coupling to the Mitogen-activated Protein (MAP) Kinase Signaling Cascade

Andreev, Julian; Galisteo, Maria L.; Kranenburg, Onno; Logan, Susan K.; Chiu, Ernest S.; Okigaki, Mitsuhiko; Cary, Leslie A.; Moolenaar, Wouter H.; Schlessinger, Joseph

doi:10.1074/jbc.m102307200

Cited by 191 publications

(155 citation statements)

References 23 publications

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“…4, B and D). Interestingly, Pyk2 and Src were implicated in promoting EGFR transactivation (4,38). The fact that these tyrosine phosphorylation pathways are upstream of ERK is further supported by our kinetic results demonstrating that the rapid activation of Pyk2 and Src preceded ERK activation (Fig.…”

Section: Discussionsupporting

confidence: 69%

Vasopressin-mediated mitogenic signaling in intestinal epithelial cells

Chiu

Santiskulvong

et al. 2002

American Journal of Physiology-Cell Physiology

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Here, we demonstrate that arginine vasopressin (AVP) induces multiple intracellular signal transduction pathways in rat intestinal epithelial IEC-18 cells via a V 1A receptor. Addition of AVP to these cells induces a rapid and transient increase in cytosolic Ca 2ϩ concentration and promotes protein kinase D (PKD) activation through a protein kinase C (PKC)-dependent pathway, as revealed by in vitro kinase assays and immunoblotting with an antibody that recognizes autophosphorylated PKD at Ser 916 . AVP also stimulates the tyrosine phosphorylation of the nonreceptor tyrosine kinase proline-rich tyrosine kinase 2 (Pyk2) and promotes Src family kinase phosphorylation at Tyr 418 , indicative of Src activation. AVP induces extracellular signal-related kinase (ERK)-1 (p44 mapk ) and ERK-2 (p42 mapk ) activation, a response prevented by treatment with mitogen-activated protein kinase kinase (MEK) inhibitors (PD-98059 and U-0126), specific PKC inhibitors (GF-I and Ro-31-8220), depletion of Ca 2ϩ (EGTA and thapsigargin), selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (tyrphostin AG-1478, compound 56), or the selective Src family kinase inhibitor PP-2. Furthermore, AVP acts as a potent growth factor for IEC-18 cells, inducing DNA synthesis and cell proliferation through ERK-, Ca 2ϩ -, PKC-, EGFR tyrosine kinase-, and Src-dependent pathways. arginine vasopressin; protein kinase D; protein kinase C; Src; proline-rich tyrosine kinase 2; intestinal epithelial proliferation THE SEQUENTIAL PROLIFERATION, lineage-specific differentiation, migration, and cell death of epithelial cells of the intestinal mucosa is a tightly regulated process that is modulated by a broad spectrum of regulatory peptides (8,36,70). The nontransformed IEC-6 and IEC-18 cells, derived from rat small intestinal crypt (56), have provided an in vitro model to examine intestinal epithelial cell migration, differentiation, and proliferation (16,27,58,70). Previous studies demonstrated that the proliferation and migration of these intestinal epithelial cells is regulated by a variety of polypeptide growth factors, including epidermal growth factor (EGF), insulin-like growth factor I, and hepatocyte growth factor, which act via single-pass transmembrane tyrosine kinase receptors (3,17,51). Neuropeptides and vasoactive peptides that signal through G protein-coupled receptors (GPCRs), characterized by seven-transmembrane helices, also act as potent cellular growth factors for a variety of cell types (63,64,66,67). However, the role of GPCRs and their ligands in intestinal epithelial cell signaling and proliferation remains poorly understood.The neurohypophysial nonapeptide arginine vasopressin (AVP), also known as antidiuretic hormone, is traditionally recognized for its role as a vasoconstrictor hormone acting on vascular smooth muscle cells and its antidiuretic effect via the renal collecting system. In addition to its function in the regulation of body fluid osmolality, vascular tone, and blood pressure, AVP acts as a growth-promo...

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Section: Discussionsupporting

confidence: 69%

Vasopressin-mediated mitogenic signaling in intestinal epithelial cells

Chiu

Santiskulvong

et al. 2002

American Journal of Physiology-Cell Physiology

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“…Our data also showed that pp2 had no impacts on the phosphorylation of JNK, p38 MAPK, and FAK, suggesting that these pathways may not be involved in the Src-mediated survival either. There have been reports that Pyk2 may be a substrate of Src (Andreev et al, 2001;Li et al, 2001). In our study, we found that pp2 could significantly inhibit the phosphorylation of Pyk2 when it induced cell death in the lung tumor cells (Figure 9), suggesting that Pyk2 might be a downstream effecter of Src, through which Src functions to protect lung tumor cells from anoikis.…”

Section: Activated Src Protects Lung Tumor Cells From Anoikis Throughsupporting

confidence: 49%

Altered regulation of Src upon cell detachment protects human lung adenocarcinoma cells from anoikis

Lin

Zhang

et al. 2004

Oncogene

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Src plays an important role in cell proliferation, differentiation, adhesion, and migration. Altered Src activity has been strongly implicated in the development, growth, progression, and metastasis of human cancers. We have analysed the change and regulation of Src upon cell detachment in anoikis-resistant human lung adenocarcinoma cells and compared with that of relatively normal and anoikis-sensitive epithelial cells. We found that Src activity was increased in the anoikis-resistant lung tumor cells when they were detached and cultured in suspension. The detachment-induced Src activation in the tumor cells compensates for the loss of cell survival signals caused by disruption of cell-matrix interactions and contributes to anoikis resistance of the tumor cells. Pyk2, rather than PI 3K/Akt or Erk, appears to be the key downstream effecter of Src in mediating the cell survival signals. The increased Src activity is mainly due to the phosphorylation of Tyr-419, rather than the dephosphorylation of Tyr-530 of Src protein. PDGFR, not FAK or EGFR, appears to be the upstream protein tyrosine kinase responsible for the detachment-induced Src activation in the lung tumor cells. The increased Src activity upon cell detachment may contribute to the metastasis potential of malignant tumors.

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“…The lack of complete inhibition in the presence of ATP could be due to the fact that it is in excess compared to the concentration released by injury. Alternatively, other studies have shown that phosphorylation of ERK may occur via P2YRs and other GPCRs and be independent of EGFR (Andreev, et al, 2001;Montiel, et al, 2006) (Figure 7).…”

Section: Discussionmentioning

confidence: 97%

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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Src and Pyk2 Mediate G-protein-coupled Receptor Activation of Epidermal Growth Factor Receptor (EGFR) but Are Not Required for Coupling to the Mitogen-activated Protein (MAP) Kinase Signaling Cascade

Cited by 191 publications

References 23 publications

Vasopressin-mediated mitogenic signaling in intestinal epithelial cells

Vasopressin-mediated mitogenic signaling in intestinal epithelial cells

Altered regulation of Src upon cell detachment protects human lung adenocarcinoma cells from anoikis

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

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