scholarly journals Distinct requirements for the Sprouty domain for functional activity of Spred proteins

2005 ◽  
Vol 388 (2) ◽  
pp. 445-454 ◽  
Author(s):  
James A. J. KING ◽  
Andrew F. L. STRAFFON ◽  
Giovanna M. D'ABACO ◽  
Carole L. C. POON ◽  
Stacey T. T. I ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Cycle Progression ◽  
Mapk Pathway ◽  
Receptor Activation ◽  
Small Gtpases ◽  
Mitogen Activated Protein Kinase ◽  
Functional Roles ◽  
Inhibitory Function ◽  
Mitogen Activated Protein ◽  
Growth Factor Signalling

Sprouty and Spred {Sprouty-related EVH1 [Ena/VASP (vasodilator-stimulated phosphoprotein) homology 1] domain} proteins have been identified as antagonists of growth factor signalling pathways. We show here that Spred-1 and Spred-2 appear to have distinct mechanisms whereby they induce their effects, as the Sprouty domain of Spred-1 is not required to block MAPK (mitogen-activated protein kinase) activation, while that of Spred-2 is required. Similarly, deletion of the C-terminal Sprouty domain of Spred-1 does not affect cell-cycle progression of G0-synchronized cells through to S-phase following growth factor stimulation, while the Sprouty domain is required for Spred-2 function. We also demonstrate that the inhibitory function of Spred proteins is restricted to the Ras/MAPK pathway, that tyrosine phosphorylation is not required for this function, and that the Sprouty domain mediates heterodimer formation of Spred proteins. Growth-factor-mediated activation of the small GTPases, Ras and Rap1, was able to be regulated by Spred-1 and Spred-2, without affecting receptor activation. Taken together, these results highlight the potential for different functional roles of the Sprouty domain within the Spred family of proteins, suggesting that Spred proteins may use different mechanisms to induce inhibition of the MAPK pathway.

MEK and RAF inhibitors for BRAF-mutated cancers

2012 ◽  
Vol 14 ◽  
Author(s):  
Sarah Belden ◽  
Keith T. Flaherty
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Drug Targets ◽  
Mapk Pathway ◽  
Growth Factor Receptor ◽  
Receptor Activation ◽  
Mitogen Activated Protein Kinase ◽  
Braf Mutations ◽  
Mitogen Activated Protein ◽  
Pharmacologic Inhibition

The mitogen-activated protein kinase (MAPK) pathway has been implicated in the pathophysiology of many cancers. Under normal physiologic conditions, the RAS–RAF–mitogen-activated protein kinase kinase (MEK)–mitogen-activated protein kinase (ERK) signalling cascade interaction is initiated by ligation of a receptor-linked tyrosine kinase by its cognate growth factor. It has been demonstrated in many systems that aberrant autocrine or paracrine stimulation of growth factor receptors is pathogenic in large part because of MAPK activation. As one of the key downstream effector pathways of mutated RAS (KRAS,NRASandHRAS), pharmacologic inhibition of components of the MAPK pathway has been pursued as a means to indirectly inhibit RAS, which remains a technical challenge for direct pharmacologic inhibition. RAF and MEK are the two non-membrane-bound, serine–threonine and tyrosine–threonine kinases, within the pathway that have been most extensively explored as drug targets. The discovery of activating BRAF mutations in cancer clarified which cancer types and subsets of certain cancers are most dependent on activation of the MAPK pathway for growth and survival. Now, with the successful translation of selective BRAF and MEK inhibitors into validated therapies for BRAF mutant melanoma, the field seeks to resolve the role for these agents in cancers harbouring RAS mutations or those driven by aberrant growth factor receptor activation.

Sprouty proteins: antagonists of endothelial cell signaling and more

2003 ◽  
Vol 90 (10) ◽  
pp. 586-590 ◽  
Author(s):  
Miguel Cabrita ◽  
Gerhard Christofori
Keyword(s):  
Growth Factor ◽  
Mapk Pathway ◽  
Medical Science ◽  
Receptor Activation ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Dual Function ◽  
Vegf Receptor ◽  
Mapk Activation ◽  
Binding Partners

SummaryAmong many signaling pathways, receptor tyrosine kinases (RTKs) can activate the mitogen-activated protein kinase (MAPK) signaling pathway that subsequently leads to a variety of cellular changes, including proliferation, differentiation and motility. The regulation of growth factor signaling is complex, and various cell types respond differently to the same stimulus for reasons not entirely understood. The recent discovery in Drosophila of Sprouty (dSpry), an inhibitor of RTK-induced MAPK activation, provides clues to how these signals are regulated. In mammals, four orthologues of dSpry, Spry1-4, have been described, and in this review we discuss their functional characteristics. Mammalian Sprys, like dSpry, are ligand-induced feedback inhibitors of a number of growth factor receptors. In endothelial cells, upon fibroblast growth factor (FGF) receptor and vascular endothelial growth factor (VEGF) receptor activation, Sprys translocate to the plasma membrane and inhibit cell growth and proliferation. However, in epidermal growth factor (EGF)-stimulated cells, Sprys can enhance MAPK activation. In addition, Sprys have many binding partners, including different effectors of the MAPK activation pathway. The intersection point where Sprys interfere in the MAPK pathway as well as their interactions with other proteins may partly explain the dual, yet opposing roles, on growth factor-induced MAPK activation. Moreover, Sprys require tyrosine phosphorylation to interact with their binding partners, a prerequisite for their dual function. Hence, Sprys add another layer of complexity to the regulation of RTK-mediated signal transduction that begins to explain the variation in cellular responses to growth factors.This publication was partially financed by Serono Foundation for the Advancement of Medical Science.Part of this paper was originally presented at the 2nd International Workshop on New Therapeutic Targets in Vascular Biology from February 6-9, 2003 in Geneva, Switzerland.

Activation of the insulin receptor (IR) by insulin and a synthetic peptide has different effects on gene expression in IR-transfected L6 myoblasts

2008 ◽  
Vol 412 (3) ◽  
pp. 435-445 ◽  
Author(s):  
Maja Jensen ◽  
Jane Palsgaard ◽  
Rehannah Borup ◽  
Pierre de Meyts ◽  
Lauge Schäffer
Keyword(s):  
Gene Expression ◽  
Insulin Receptor ◽  
Mapk Pathway ◽  
Receptor Activation ◽  
Mitogen Activated Protein Kinase ◽  
Single Chain ◽  
Therapeutic Implications ◽  
Insulin Mimetic ◽  
Mitogen Activated Protein

Single-chain peptides have been recently produced that display either mimetic or antagonistic properties against the insulin and IGF-1 (insulin-like growth factor 1) receptors. We have shown previously that the insulin mimetic peptide S597 leads to significant differences in receptor activation and initiation of downstream signalling cascades despite similar binding affinity and in vivo hypoglycaemic potency. It is still unclear how two ligands can initiate different signalling responses through the IR (insulin receptor). To investigate further how the activation of the IR by insulin and S597 differentially activates post-receptor signalling, we studied the gene expression profile in response to IR activation by either insulin or S597 using microarray technology. We found striking differences between the patterns induced by these two ligands. Most remarkable was that almost half of the genes differentially regulated by insulin and S597 were involved in cell proliferation and growth. Insulin either selectively regulated the expression of these genes or was a more potent regulator. Furthermore, we found that half of the differentially regulated genes interact with the genes involved with the MAPK (mitogen-activated protein kinase) pathway. These findings support our signalling results obtained previously and confirm that the main difference between S597 and insulin stimulation resides in the activation of the MAPK pathway. In conclusion, we show that insulin and S597 acting via the same receptor differentially affect gene expression in cells, resulting in a different mitogenicity of the two ligands, a finding which has critical therapeutic implications.

scholarly journals Platelet-derived growth factor activation of mitogen-activated protein kinase depends on the sequential activation of phosphatidylcholine-specific phospholipase C, protein kinase C-ζ and Raf-1

1997 ◽  
Vol 325 (2) ◽  
pp. 303-307 ◽  
Author(s):  
Marc C. M. VAN DIJK ◽  
Henk HILKMANN ◽  
Wim J. VAN BLITTERSWIJK
Keyword(s):  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Phospholipase C ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Platelet Derived Growth Factor ◽  
Kinase C ◽  
Mitogen Activated Protein ◽  
Pkc Ζ

The mechanism of Raf-1 activation by platelet-derived growth factor (PDGF) is poorly defined. We previously reported that, in Rat-1 fibroblasts, PDGF activates a phosphatidylcholine-specific phospholipase C (PC-PLC) and that the product, diacylglycerol, somehow activates protein kinase C-ζ (PKC-ζ). Both PC-PLC and PKC-ζ activities were required for PDGF activation of mitogen-activated protein kinase (MAPK). Now we report that MAPK activation by exogenous PC-PLC depends on Raf-1 activation. PKC-ζ co-immunoprecipitates with, phoshorylates and activates Raf-1, suggesting that in the PDGF- and PC-PLC-activated MAPK pathway, PKC-ζ operates in a signalling complex as a direct activator of Raf-1.

Receptor tyrosine kinase–GPCR signal complexes

2003 ◽  
Vol 31 (6) ◽  
pp. 1220-1225 ◽  
Author(s):  
N.J. Pyne ◽  
C. Waters ◽  
N.A. Moughal ◽  
B.S. Sambi ◽  
S. Pyne
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
Mapk Pathway ◽  
Receptor Activation ◽  
Mitogen Activated Protein Kinase ◽  
S1p1 Receptor ◽  
Receptor Complexes ◽  
Molecular Events ◽  
Lpa1 Receptor ◽  
Trk A

The formation of complexes between growth factor receptors and members of a family of G-protein-coupled receptors whose natural ligands are S1P (sphingosine 1-phosphate) and LPA (lysophosphatidic acid) represents a new signalling entity. This receptor complex allows for integrated signalling in response to growth factor and/or S1P/LPA and provides a mechanism for more efficient activation (due to integrated close-proximity signalling from both receptor classes) of the p42/p44 MAPK (mitogen-activated protein kinase) pathway. This article provides information on the molecular events at the interface between receptor tyrosine kinases and S1P/LPA receptors. Examples include the PDGF (platelet-derived growth factor)-induced tyrosine phosphorylation of Giα, released upon S1P1 receptor activation, which is required for initiation of the p42/p44 MAPK pathway. Critical to this event is the formation of endocytic vesicles containing functionally active PDGFβ receptor–S1P1 receptor complexes, which are internalized and relocated with components of the p42/p44 MAPK pathway. We also report examples of cross-talk signal integration between the Trk A (tropomyosin receptor kinase A) receptor and the LPA1 receptor in terms of the NGF (nerve growth factor)-dependent regulation of the p42/p44 MAPK pathway. NGF induces recruitment of the LPA1 receptor to the nucleus (delivery might be Trk A-dependent), whereupon the LPA1 receptor may govern gene expression via novel nuclear signalling processes.

scholarly journals Epidermal Growth Factor Signaling and Mitogenesis inPlcg1 Null Mouse Embryonic Fibroblasts

1998 ◽  
Vol 9 (4) ◽  
pp. 749-757 ◽  
Author(s):  
Qun-sheng Ji ◽  
Sandra Ermini ◽  
Josep Baulida ◽  
Feng-lei Sun ◽  
Graham Carpenter
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Receptor Activation ◽  
Mitogen Activated Protein Kinase ◽  
Null Mouse ◽  
Growth Factor Signaling ◽  
Mitogen Activated Protein ◽  
Epidermal Growth ◽  
Early Mouse

Gene targeting techniques and early mouse embryos have been used to produce immortalized fibroblasts genetically deficient in phospholipase C (PLC)-γ1, a ubiquitous tyrosine kinase substrate.Plcg1 −/− embryos die at embryonic day 9; however, cells derived from these embryos proliferate as well as cells from Plcg1 +/+ embryos. The null cells do grow to a higher saturation density in serum-containing media, as their capacity to spread out is decreased compared with that of wild-type cells. In terms of epidermal growth factor receptor activation and internalization, or growth factor induction of mitogen-activated protein kinase, c-fos, or DNA synthesis in quiescent cells, PLcg1 −/− cells respond equivalently to PLcg1 +/+ cells. Also, null cells are able to migrate effectively in a wounded monolayer. Therefore, immortalized fibroblasts do not require PLC-γ1 for many responses to growth factors.

Role of platelet-derived growth factor-B, vascular endothelial growth factor, insulin-like growth factor-II, mitogen-activated protein kinase and transforming growth factor-β1 in expansion-induced lung growth in fetal sheep

2006 ◽  
Vol 18 (6) ◽  
pp. 655 ◽  
Author(s):  
Megan J. Wallace ◽  
Alison M. Thiel ◽  
Andrea M. Lines ◽  
Graeme R. Polglase ◽  
Foula Sozo ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Mapk Pathway ◽  
Fetal Lung ◽  
Mitogen Activated Protein Kinase ◽  
Insulin Like Growth Factor ◽  
Lung Expansion ◽  
Mitogen Activated Protein ◽  
Extracellular Matrix Remodelling ◽  
Tgf Β1

Increased fetal lung expansion induces lung growth, cell differentiation and extracellular matrix remodelling, although the mechanisms involved are unknown. Platelet-derived growth factor (PDGF)-B, vascular endothelial growth factor (VEGF) and insulin-like growth factor (IGF)-II are mitogens activating the mitogen-activated protein kinase (MAPK) pathway, whereas transforming growth factor (TGF)-β1 induces differentiation and extracellular matrix remodelling. In the present study, we investigated the mRNA levels of PDGF-B, VEGF, IGF-II and TGF-β1, as well as active MAPK levels, during increased fetal lung expansion induced by tracheal obstruction (TO) in sheep for 0 (controls), 36 h or 2, 4, or 10 days (n = 5 in each group). The 3.7-kb VEGF transcript increased by 30% (P < 0.05) at 36 h TO. The expression of PDGF-B decreased by approximately 25% (P < 0.01) at 2–10 days TO. In contrast, TGF-β1 mRNA increased by 96% (P < 0.05) at 10 days TO, when bioactive TGF-β1 decreased by 55% (P < 0.05). Insulin-like growth factor-II mRNA tended to increase at 10 days TO (37% above controls; P = 0.07), whereas mRNA for its receptor, IGF1R, was reduced by TO. There was no change in active MAPK levels preceding or at the time of a TO-induced 800% increase in cell proliferation. We conclude that VEGF is likely to promote expansion-induced endothelial cell proliferation, but the mechanisms underlying expansion-induced proliferation of fibroblasts and alveolar epithelial cells are unlikely to be mediated by increases in PDGF-B or IGF-II expression or activation of the MAPK pathway.

Role of tyrosine kinase and p44/42 MAPK in D2-like receptor-mediated stimulation of Na+, K+-ATPase in kidney

2002 ◽  
Vol 282 (4) ◽  
pp. F697-F702 ◽  
Author(s):  
Vihang Narkar ◽  
Tahir Hussain ◽  
Mustafa Lokhandwala
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Rat Kidney ◽  
Receptor Activation ◽  
Proximal Tubules ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Stimulation Of

Our laboratory has shown that dopamine D2-like receptor activation causes stimulation of Na+, K+-ATPase (NKA) activity in the proximal tubules of the rat kidney. The present study was designed to investigate the cellular signaling mechanisms mediating this response to D2-like receptor activation. We measured the stimulation of NKA activity by bromocriptine (D2-like receptor agonist) in the absence and presence of PD-98059 [p44/42 mitogen-activated protein kinase (MAPK) kinase inhibitor] and genistein (tyrosine kinase inhibitor) in renal proximal tubules. Both agents inhibited bromocriptine-mediated stimulation of NKA, suggesting the involvement of p44/42 MAPK and tyrosine kinase in this response. Additionally, we found that bromocriptine increased the phosphorylation of p44/42 MAPK in the proximal tubules, which was blocked by PD-98059 and genistein. These results show that D2-like receptor activation causes stimulation of NKA activity by means of a tyrosine kinase-p44/42 MAPK pathway in the proximal tubules of the kidney.

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