scholarly journals Off-target inhibition by active site-targeting SHP2 inhibitors

2018 ◽  
Author(s):  
Ryouhei Tsutsumi ◽  
Hao Ran ◽  
Benjamin G. Neel
Keyword(s):  
Growth Factor ◽  
Active Site ◽  
Tyrosine Phosphatase ◽  
Growth Factor Receptor ◽  
Sh2 Domain ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Cellular Context ◽  
Site Targeting

AbstractDue to the involvement of SHP2 (SH2 domain-containing protein tyrosine phosphatase) in human disease, including Noonan syndrome and cancer, several inhibitors targeting SHP2 have been developed. Here, we report that the commonly used SHP2 inhibitor NSC-78788 does not exhibit robust inhibitory effects on growth factor-dependent MAPK (mitogen-activated protein kinase) pathway activation, and that the recently developed active site-targeting SHP2 inhibitors IIB-08, 11a-1, and GS-493 show off-target effects on ligand-evoked activation/trans-phosphorylation of the PDGFRβ (platelet-derived growth factor receptor β). GS-493 also inhibits purified human PDGFRβ and SRC in vitro, whereas PDGFRβ inhibition by IIB-08 and 11a-1 occurs only in the cellular context. Our results argue for extreme caution in inferring specific functions for SHP2 based on studies using these inhibitors.

scholarly journals Functional co-operation between the subunits in heterodimeric platelet-derived growth factor receptor complexes

1999 ◽  
Vol 341 (3) ◽  
pp. 523-528 ◽  
Author(s):  
Muhammad EMADUDDIN ◽  
Simon EKMAN ◽  
Lars RÖNNSTRAND ◽  
Carl-Henrik HELDIN
Keyword(s):  
Growth Factor ◽  
Growth Factor Receptor ◽  
Sh2 Domain ◽  
Mitogen Activated Protein Kinase ◽  
Platelet Derived Growth Factor ◽  
Wild Type ◽  
Signalling Molecules ◽  
Receptor Complexes ◽  
Mitogen Activated Protein ◽  
Docking Sites

To determine the importance of the phosphorylation capacity of receptor kinase as well as the ability to serve as docking sites for SH2-domain-containing signal transduction molecules, we established pig aortic endothelial cell lines stably expressing kinase-active platelet-derived growth factor (PDGF) α-receptors together with kinase-inactive β-receptors, and vice versa. After stimulation with PDGF-AB, heterodimeric receptor complexes were formed in which the kinase-inactive receptor was phosphorylated by the kinase-active receptor, although less efficiently than in heterodimers of wild-type receptors. The kinase-active receptor was only minimally phosphorylated. Thus the phosphorylation within the receptor dimer occurred in trans between the components. Analyses of the abilities of heterodimeric receptor complexes of one kinase-active and one kinase-inactive receptor to mediate mitogenicity, chemotaxis and activation of mitogen-activated protein kinase revealed less efficient effects than those of heterodimers of wild-type receptors. Importantly, however, the fact that signalling capacities were retained illustrates a functional co-operation between the two receptor molecules in the dimer, where one receptor provides a functional kinase and the other acts as a substrate and provides docking sites for downstream signalling molecules.

scholarly journals The Importance of the Right Framework: Mitogen-Activated Protein Kinase Pathway and the Scaffolding Protein PTPIP51

2018 ◽  
Vol 19 (10) ◽  
pp. 3282 ◽  
Author(s):  
Eric Dietel ◽  
Alexander Brobeil ◽  
Stefan Gattenlöhner ◽  
Monika Wimmer
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Tyrosine Phosphatase ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Epidermal Growth

The protein tyrosine phosphatase interacting protein 51 (PTPIP51) regulates and interconnects signaling pathways, such as the mitogen-activated protein kinase (MAPK) pathway and an abundance of different others, e.g., Akt signaling, NF-κB signaling, and the communication between different cell organelles. PTPIP51 acts as a scaffold protein for signaling proteins, e.g., Raf-1, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (Her2), as well as for other scaffold proteins, e.g., 14-3-3 proteins. These interactions are governed by the phosphorylation of serine and tyrosine residues of PTPIP51. The phosphorylation status is finely tuned by receptor tyrosine kinases (EGFR, Her2), non-receptor tyrosine kinases (c-Src) and the phosphatase protein tyrosine phosphatase 1B (PTP1B). This review addresses various diseases which display at least one alteration in these enzymes regulating PTPIP51-interactions. The objective of this review is to summarize the knowledge of the MAPK-related interactome of PTPIP51 for several tumor entities and metabolic disorders.

scholarly journals Direct recruitment of CRK and GRB2 to VEGFR-3 induces proliferation, migration, and survival of endothelial cells through the activation of ERK, AKT, and JNK pathways

Blood ◽  
2005 ◽  
Vol 106 (10) ◽  
pp. 3423-3431 ◽  
Author(s):  
Ahmad Salameh ◽  
Federico Galvagni ◽  
Monia Bardelli ◽  
Federico Bussolino ◽  
Salvatore Oliviero
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Umbilical Vein ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Capillary Plexus ◽  
Primary Capillary Plexus ◽  
Umbilical Vein Endothelial Cells

AbstractVascular endothelial growth factor receptor-3 (VEGFR-3) plays a key role for the remodeling of the primary capillary plexus in the embryo and contributes to angiogenesis and lymphangiogenesis in the adult. However, VEGFR-3 signal transduction pathways remain to be elucidated. Here we investigated VEGFR-3 signaling in primary human umbilical vein endothelial cells (HUVECs) by the systematic mutation of the tyrosine residues potentially involved in VEGFR-3 signaling and identified the tyrosines critical for its function. Y1068 was shown to be essential for the kinase activity of the receptor. Y1063 signals the receptor-mediated survival by recruiting CRKI/II to the activated receptor, inducing a signaling cascade that, via mitogen-activated protein kinase kinase-4 (MKK4), activates c-Jun N-terminal kinase-1/2 (JNK1/2). Inhibition of JNK1/2 function either by specific peptide inhibitor JNKI1 or by RNA interference (RNAi) demonstrated that activation of JNK1/2 is required for a VEGFR-3–dependent prosurvival signaling. Y1230/Y1231 contributes, together with Y1337, to proliferation, migration, and survival of endothelial cells. Phospho-Y1230/Y1231 directly recruits growth factor receptor–bonus protein (GRB2) to the receptor, inducing the activation of both AKT and extracellular signal–related kinase 1/2 (ERK1/2) signaling. Finally, we observed that Y1063 and Y1230/Y1231 signaling converge to induce c-JUN expression, and RNAi experiments demonstrated that c-JUN is required for growth factor–induced prosurvival signaling in primary endothelial cells.

scholarly journals Regulation of EphB2 activation and cell repulsion by feedback control of the MAPK pathway

2008 ◽  
Vol 183 (5) ◽  
pp. 933-947 ◽  
Author(s):  
Alexei Poliakov ◽  
Maria L. Cotrina ◽  
Andrea Pasini ◽  
David G. Wilkinson
Keyword(s):  
Feedback Loop ◽  
Fibroblast Growth Factor Receptor ◽  
Mapk Pathway ◽  
Tyrosine Phosphatase ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Eph Receptor ◽  
Mitogen Activated Protein ◽  
Mediate Cell ◽  
Cell Repulsion

In this study, we investigated whether the ability of Eph receptor signaling to mediate cell repulsion is antagonized by fibroblast growth factor receptor (FGFR) activation that can promote cell invasion. We find that activation of FGFR1 in EphB2-expressing cells prevents segregation, repulsion, and collapse responses to ephrinB1 ligand. FGFR1 activation leads to increased phosphorylation of unstimulated EphB2, which we show is caused by down-regulation of the leukocyte common antigen–related tyrosine phosphatase receptor that dephosphorylates EphB2. In addition, FGFR1 signaling inhibits further phosphorylation of EphB2 upon stimulation with ephrinB1, and we show that this involves a requirement for the mitogen-activated protein kinase (MAPK) pathway. In the absence of activated FGFR1, EphB2 activates the MAPK pathway, which in turn promotes EphB2 activation in a positive feedback loop. However, after FGFR1 activation, the induction of Sprouty genes inhibits the MAPK pathway downstream of EphB2 and decreases cell repulsion and segregation. These findings reveal a novel feedback loop that promotes EphB2 activation and cell repulsion that is blocked by transcriptional targets of FGFR1.

Activation of c-fos gene expression by a kinase-deficient epidermal growth factor receptor

1994 ◽  
Vol 14 (11) ◽  
pp. 7527-7534
Author(s):  
E R Eldredge ◽  
G M Korf ◽  
T A Christensen ◽  
D C Connolly ◽  
M J Getz ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Transcriptional Activation ◽  
Kinase Activity ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Tyrosine Kinase Activity ◽  
Mitogen Activated Protein ◽  
Epidermal Growth ◽  
Ligand Stimulation

The intrinsic tyrosine kinase activity of the epidermal growth factor receptor (EGFR) has been shown to be responsible for many of the pleiotropic intracellular effects resulting from ligand stimulation [W.S. Chen, C.S. Lazar, M. Poenie, R.Y. Tsien, G.N. Gill, and M.G. Rosenfeld, Nature (London) 328:820-823, 1987; A.M. Honegger, D. Szapary, A. Schmidt, R. Lyall, E. Van Obberghen, T.J. Dull, A. Ulrich, and J. Schlessinger, Mol. Cell. Biol. 7:4568-4571, 1987]. Recently, however, it has been shown that addition of ligand to cells expressing kinase-defective EGFR mutants can result in the phosphorylation of mitogen-activated protein kinase (R. Campos-González and J.R. Glenney, Jr., J. Biol. Chem. 267:14535-14538, 1992; E. Selva, D.L. Raden, and R.J. Davis, J. Biol. Chem. 268:2250-2254, 1993), as well as stimulation of DNA synthesis (K.J. Coker, J.V. Staros, and C.A. Guyer, Proc. Natl. Acad. Sci. USA 91:6967-6971, 1994). Moreover, mitogen-activated protein kinase has been shown to phosphorylate the transcription factor p62TCF in vitro, leading to enhanced ternary complex formation between p62TCF, p67SRF, and the c-fos serum response element (SRE) [H. Gille, A.D. Sharrocks, and P.E. Shaw, Nature (London) 358:414-417, 1992]. On the basis of these observations, we have investigated the possibility that the intrinsic tyrosine kinase activity of the EGFR may not be necessary for transcriptional activation mediated via p62TCF. Here, we demonstrate that a kinase-defective EGFR mutant can signal ligand-induced expression of c-fos protein and that a significant component of this induction appears to be mediated at the transcriptional level. Investigation of transcriptional activation mediated by the c-fos SRE shows that this response is impaired by mutations in the SRE which eliminate binding of p62(TCF). These data indicate that information inherent in the structure of the EGFR can be accessed by ligand stimulation independent of the receptor's catalytic kinase function.

scholarly journals Phosphorylation sites at the C-terminus of the platelet-derived growth factor receptor bind phospholipase C gamma 1.

1993 ◽  
Vol 4 (1) ◽  
pp. 49-57 ◽  
Author(s):  
A Kashishian ◽  
J A Cooper
Keyword(s):  
Growth Factor ◽  
Phospholipase C ◽  
Tyrosine Phosphorylation ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Platelet Derived Growth Factor ◽  
Phosphorylation Sites ◽  
C Terminus ◽  
Mitogen Activated Protein ◽  
Src Homology

We have identified two tyrosine phosphorylation sites, Tyr 1009 and Tyr 1021, in the C-terminal noncatalytic region of the human platelet-derived growth factor (PDGF) receptor beta subunit. Mutant receptors with phenylalanine substitutions at either or both of these tyrosines were expressed in dog epithelial cells. Mutation of Tyr 1021 markedly reduced the PDGF-stimulated binding of phospholipase C (PLC) gamma 1 but had no effect on binding of the GTPase activator protein of Ras or of phosphatidylinositol 3 kinase. Mutation of Tyr 1009 reduced binding of PLC gamma 1 less severely. Mutation of Tyr 1021, or both Tyr 1009 and Tyr 1021, also reduced the PDGF-dependent binding of a transiently expressed fusion protein containing the two Src-homology 2 domains from PLC gamma 1. Mutation of Tyr 1021, or both Tyr 1009 and Tyr 1021, greatly reduced PDGF-stimulated tyrosine phosphorylation of PLC gamma 1 but did not prevent the tyrosine phosphorylation of other cell proteins, including mitogen-activated protein kinase. We conclude that Tyr 1021, and possibly Tyr 1009, is a binding site for PLC gamma 1.

Sign in / Sign up

Export Citation Format

Share Document