Opposing Actions of CSW and RasGAP Modulate the Strength of Torso RTK Signaling in the Drosophila Terminal Pathway

Cleghon, Vaughn; Feldmann, Pascale; Ghiglione, Christian; Copeland, Terry D.; Perrimon, Norbert; Hughes, David A.; Morrison, Deborah K.

doi:10.1016/s1097-2765(00)80287-7

Cited by 90 publications

(71 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Results of biochemical analyses of Gab-SHP-2 interaction as well as those of genetic studies on the Drosophila SHP-2 homologue Corkscrew indicate that SHP-2 is capable of activating Ras (61,62). Consistently, SHP-2 has been reported to bind the Grb2-Sos complex (43,44), the membrane localization of which results in the activation of the Ras/Raf/Mek/Erk pathway.…”

Section: Discussionmentioning

confidence: 86%

Helicobacter pylori CagA Induces Ras-independent Morphogenetic Response through SHP-2 Recruitment and Activation

Higashi

Nakaya

Tsutsumi

et al. 2004

Journal of Biological Chemistry

256

242

View full text Add to dashboard Cite

The CagA protein of Helicobacter pylori, which is injected from the bacteria into bacteria-attached gastric epithelial cells, is associated with gastric carcinoma. CagA is tyrosine-phosphorylated by Src family kinases, binds the SH2 domain-containing SHP-2 phosphatase in a tyrosine phosphorylation-dependent manner, and deregulates its enzymatic activity. We established AGS human gastric epithelial cells that inducibly express wildtype or a phosphorylation-resistant CagA, in which tyrosine residues constituting the EPIYA motifs were substituted with alanines. Upon induction, wild-type CagA, but not the mutant CagA, elicited strong elongation of cell shape, termed the "hummingbird" phenotype. Time-lapse video microscopic analysis revealed that the CagA-expressing cells exhibited a marked increase in cell motility with successive rounds of elongation-contraction processes. Inhibition of CagA phosphorylation by an Src kinase inhibitor, PP2, or knockdown of SHP-2 expression by small interference RNA (siRNA) abolished the CagA-mediated hummingbird phenotype. The morphogenetic activity of CagA also required Erk MAPK but was independent of Ras or Grb2. In AGS cells, CagA prolonged duration of Erk activation in response to serum stimulation. Conversely, inhibition of SHP-2 expression by siRNA abolished the sustained Erk activation. Thus, SHP-2 acts as a positive regulator of Erk activity in AGS cells. These results indicate that SHP-2 is involved in the Ras-independent modification of Erk signals that is necessary for the morphogenetic activity of CagA. Our work therefore suggests a key role of SHP-2 in the pathological activity of H. pylori virulence factor CagA.

show abstract

Section: Discussionmentioning

confidence: 86%

Helicobacter pylori CagA Induces Ras-independent Morphogenetic Response through SHP-2 Recruitment and Activation

Higashi

Nakaya

Tsutsumi

et al. 2004

Journal of Biological Chemistry

256

242

View full text Add to dashboard Cite

show abstract

“…9 Similarly, the Drosophila ortholog of SHP2, Corkscrew, transduces the Torso RTK signaling by blocking Ras inactivation. 10 Other reports also show that SHP2 dephosphorylates a RasGAPbinding site on the adapter protein Gab1, 11 leading to the same conclusion that SHP2 promotes Ras activation by blocking RasGAP. Furthermore, SHP2 promotes Ras and ERK1/2 activation by facilitating RTK-induced activation of the Src family kinases (SFKs).…”

mentioning

confidence: 84%

Inhibition of SHP2 leads to mesenchymal to epithelial transition in breast cancer cells

Agazie

2008

Cell Death Differ

View full text Add to dashboard Cite

The Src homology phosphotyrosyl phosphatase 2 (SHP2) is an essential transducer of mitogenic and cell survival signaling in the epidermal growth factor receptor (EGFR) signaling pathway. However, the role of SHP2 in aberrant EGFR and human EGFR2 (HER2) signaling and cancer, particularly in breast cancer, has not been investigated. Here, we report that SHP2 is required for mitogenic and cell survival signaling and for sustaining the transformation phenotypes of breast cancer cell lines that overexpress EGFR and HER2. Inhibition of SHP2 suppressed EGF-induced activation of the Ras-ERK and the phosphatidylinositol 3 kinase-Akt signaling pathways, abolished anchorage-independent growth, induced epithelial cell morphology and led to reversion to a normal breast epithelial phenotype. Furthermore, inhibition of SHP2 led to upregulation of E-cadherin (epithelial marker) and downregulation of fibronectin and vimentin (mesenchymal markers). These results indicate that SHP2 promotes breast cancer cell phenotypes by positively modulating mitogenic and cell survival signaling, by suppressing E-cadherin expression which is known to play a tumor suppressor role and by sustaining the mesenchymal state as evidenced by the positive impact on fibronectin and vimentin expression. Therefore, SHP2 promotes epithelial to mesenchymal transition, whereas its inhibition leads to mesenchymal to epithelial transition. On the basis of these premises, we propose that interference with SHP2 function might help treat breast cancer.

show abstract

“…Genetic experiments in Drosophila (11) and Caenorhabditis elegans (12) and biochemical experiments in vertebrates (10) have shown that Shp2 acts upstream of the Ras/MAP kinase pathway to promote its activation. Several direct targets of Shp2 have been identified, including the platelet-derived growth factor receptors [PDGFR (13)/Torso (14)], the multiadaptor protein Gab1 (15), Csk-binding protein [Cbp/PAG (16)], and paxillin (17). Downstream of the hepatocyte growth factor/scatter factor (HGF/SF) receptor Met, Shp2 is activated by association with Gab1 and is both essential and sufficient for Met function (18,19).…”

mentioning

confidence: 99%

Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking

Hellmuth

Grosskopf

Lum

et al. 2008

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

204

182

View full text Add to dashboard Cite

The protein tyrosine phosphatase Shp2 is a positive regulator of growth factor signaling. Gain-of-function mutations in several types of leukemia define Shp2 as a bona fide oncogene. We performed a high-throughput in silico screen for small-molecular-weight compounds that bind the catalytic site of Shp2. We have identified the phenylhydrazonopyrazolone sulfonate PHPS1 as a potent and cellpermeable inhibitor, which is specific for Shp2 over the closely related tyrosine phosphatases Shp1 and PTP1B. PHPS1 inhibits Shp2-dependent cellular events such as hepatocyte growth factor/scatter factor (HGF/SF)-induced epithelial cell scattering and branching morphogenesis. PHPS1 also blocks Shp2-dependent downstream signaling, namely HGF/SF-induced sustained phosphorylation of the Erk1/2 MAP kinases and dephosphorylation of paxillin. Furthermore, PHPS1 efficiently inhibits activation of Erk1/2 by the leukemia-associated Shp2 mutant, Shp2-E76K, and blocks the anchorage-independent growth of a variety of human tumor cell lines. The PHPS compound class is therefore suitable for further development of therapeutics for the treatment of Shp2-dependent diseases.chemical biology ͉ growth factor signaling ͉ phosphatase inhibition ͉ virtual drug screening

show abstract

Opposing Actions of CSW and RasGAP Modulate the Strength of Torso RTK Signaling in the Drosophila Terminal Pathway

Cited by 90 publications

References 50 publications

Helicobacter pylori CagA Induces Ras-independent Morphogenetic Response through SHP-2 Recruitment and Activation

Helicobacter pylori CagA Induces Ras-independent Morphogenetic Response through SHP-2 Recruitment and Activation

Inhibition of SHP2 leads to mesenchymal to epithelial transition in breast cancer cells

Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking

Contact Info

Product

Resources

About