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Signalling

Drosophila Notch Signalling pathway

Summary: 

Notch signaling is involved in the modulation of Twist expression and the subdivision of the mesoderm into high and low domain of Twist. The binding of Delta leads to the cleavage and the release of the Notch intracellular domain NICD. During mesoderm specification, NICD can inhibit Twist by forming a complex with EMC, or in combination with Enhancer of split and Suppressor of hairless proteins. In this regard, we modeled the effect of Notch pathway on Twist expression. Our defined initial states reproduce biological data during mesoderm specification. When Delta is ON (high or medium signaling), the level of Twist expression can decrease from 2 to 1 or 0. When Delta is OFF (no signaling), Twist is expressed at its maximal level 2. For more details on Notch signalling pathway and it's role on Twist expression regulation during Drosophila development, see [1]; [2]; [3]; [4]; [5].


References

  1. Bate M, Rushton E.  1993.  Myogenesis and muscle patterning in Drosophila.. Comptes rendus de l'Académie des sciences. Série III, Sciences de la vie. 316(9):1047-61.
  2. Baylies MK, Bate M.  1996.  twist: a myogenic switch in Drosophila.. Science (New York, N.Y.). 272(5267):1481-4.
  3. Fuerstenberg S, Giniger E.  1998.  Multiple roles for notch in Drosophila myogenesis.. Developmental biology. 201(1):66-77.
  4. Tapanes-Castillo A, Baylies MK.  2004.  Notch signaling patterns Drosophila mesodermal segments by regulating the bHLH transcription factor twist.. Development (Cambridge, England). 131(10):2359-72.
  5. Ciglar L, Furlong EEM.  2009.  Conservation and divergence in developmental networks: a view from Drosophila myogenesis.. Current opinion in cell biology. 21(6):754-60.
Curation
Submitter: 
Abibatou MBODJ and Denis THIEFFRY

Drosophila JAK/STAT Signalling pathway

Summary: 

In Drosophila, three secreted ligands (OS, UPD2 and UPD3) have been identified for the JAK/STAT pathway. Their binding to the receptor dome induces its homo-dimerization, enabling hop to phosphorylate specific tyrosine residues of the receptor. Consequently, STAT92E is also phosphorylated by HOP, leading to his homo-dimerization and nuclear translocation. In the nucleus, STAT92E binds to target DNA sequences and acts as an activator of transcription of several target genes ([1]). During Drosophila development, the JAK/STAT pathway is involved in embryonic segmentation, eye development, cell growth, haematopoiesis, and sex determination ([2]; [3]). JAK/STAT signalling also plays important roles during spermatogenesis ([4]) and oogenesis ([5]; [6]; [3]). To study the dynamic of the pathway, we define a set of initial states representative of in vivo situations during JAK/STAT signalling. More precisely, we define a three initial states corresponding to pathway signalling (binding of OS or UPD2 or UPD3) and two initial states corresponding to pathway signalling in the presence of an inhibitor (SOCS44A or BRWD3) and one initial state corresponding to non signalling conditions (no binding of ligands).


References

  1. Hou XS, Perrimon N.  1997.  The JAK-STAT pathway in Drosophila.. Trends in genetics : TIG. 13(3):105-10.
  2. Luo H, Dearolf CR.  2001.  The JAK/STAT pathway and Drosophila development.. BioEssays : news and reviews in molecular, cellular and developmental biology. 23(12):1138-47.
  3. Johnson AN, Mokalled MH, Haden TN, Olson EN.  2011.  JAK/Stat signaling regulates heart precursor diversification in Drosophila. Development. 138(21):4627-4638.
  4. Kiger AA, Jones DL, Schulz C, Rogers MB, Fuller MT.  2001.  Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue.. Science (New York, N.Y.). 294(5551):2542-5.
  5. Denef N, Schüpbach T.  2003.  Patterning: JAK-STAT signalling in the Drosophila follicular epithelium.. Current biology : CB. 13(10):R388-90.
  6. Xi R, McGregor JR, Harrison DA.  2003.  A gradient of JAK pathway activity patterns the anterior-posterior axis of the follicular epithelium.. Developmental cell. 4(2):167-77.
Curation
Submitter: 
Abibatou MBODJ and Denis THIEFFRY

Drosophila FGF Signalling pathway

Summary: 

Drosophila genome encodes two FGF receptors, HTL (Heartless) and BTL (Breathless), which are required for the morphogenesis of different tissues. BTL is expressed in the tracheae, while HTL is expressed in embryonic mesoderm and was first identified because of its essential role in heart development. BTL ligand, BNL is encoded by the branchless gene ([1]). THS (Thisbe) and PYR (Pyramus) function in a partially redundant fashion to activate heartless (htl). Upon ligand binding receptor dimerization triggers the canonical DRK/SOS/RAS/RAF/DSOR1/RL pathway. In contrast with other RTKs, Stumps is needed to trigger signal transduction (see [2]; [3]). Stumps is a cytoplasmic protein expressed in cells also expressing the FGF receptors. The presence of an ankyrin repeat, a coiled-coil structure and many tyrosines suggests that Stumps could bind SH2 domains of proteins such as DRK or CSW ([4]). As a result, DRK recruits the guanine nucleotide exchange factor SOS (Son of sevenless), which catalyzes the exchange of GDP bound to RAS for GTP. Activated RAS then promotes the activation of RAF (Pole hole), DSOR1, and eventually that of RL (Rolled). RL can activate transcription through the inactivation of transcriptional co-repressors such as Anterior Open (AOP), as well as through the activation of transcriptional activators such as PNT (Pointed, with two forms denote by suffixes P1 and P2) ([5]; [6]). The negative regulator STY (Sprouty) acts downstream of SOS but upstream of RAS and RAF, by recruiting GAP1 and blocking the ability of DRK to bind to its positive effector. Our model enables the simulation of pathway responses to different ligand combinations. In this regard, we define four initial states to simulate different behavior of the pathway. The first initial state reproduces the signalling through the receptor HTL (bound by Pyr and Ths), the second initial state corresponds to the signalling through the receptor BTL, the third initial state corresponds to the involvement of the inhibitor Sprouty during signalling conditions and the fourth initial state corresponds to the absence of signalling (no ligands binding). Each of these initial states lead to a specific stable state representative of in vivo conditions.


References

Curation
Submitter: 
Abibatou MBODJ and Denis THIEFFRY

Drosophila Wg Signalling pathway

Summary: 

In the absence of WG, the protein complex composed by Axin, Shaggy (SGG or ZW3) and APC sequesters and ubiquitinilates Armadillo, leading to a Slmb-dependant degradation by the proteasome. In the absence of ARM, PAN binds to GRO to repress WG targets. Binding of Wingless to Arrow (ARR) or Frizzled (FZ) triggers a set of reactions, starting with the activation of Dishevelled, which in turn inhibits the AXN-SGG-APC complex. This leads (with the help of HIPK) to the accumulation and the stabilisation of ARM. Next, ARM translocates into the nucleus and binds Pangolin (PAN). Then, the ARM/PAN complex with the help of other cofactors (LGS, Nej, Pygo and Hyx) activates the transcription of WG targets. During some patterning processes as in wing disc, Nemo can inhibit PAN and thereby controls the level of WG signalling. To study dynamically the WG signalling pathway, we define two initial states corresponding to the binding of WG ligand and to the absence of binding condition. From these two initial states, we compute the resulting stable states recapitulating the activation or the non activation of the pathway, respectively. For more details on Dpp signalling pathway regulation see [1]; [2]; [3]; [4]; [5].


References

  1. Klingensmith J, Nusse R.  1994.  Signaling by wingless in Drosophila.. Developmental biology. 166(2):396-414.
  2. Michelson AM.  2003.  Running interference for hedgehog signaling.. Science's STKE : signal transduction knowledge environment. 2003(192):PE30.
  3. Perrimon N, Pitsouli C, Shilo B-Z.  2012.  Signaling mechanisms controlling cell fate and embryonic patterning.. Cold Spring Harbor perspectives in biology. 4(8):a005975.
  4. Swarup S, Verheyen EM.  2012.  Wnt/Wingless signaling in Drosophila.. Cold Spring Harbor perspectives in biology. 4(6)
  5. Tauc HM, Mann T, Werner K, Pandur P.  2012.  A role for Drosophila Wnt-4 in heart development.. Genesis (New York, N.Y. : 2000). 50(6):466-81.
Curation
Submitter: 
Abibatou MBODJ and Denis THIEFFRY

Drosophila EGF Signalling pathway

Summary: 

Four activating ligands, Spitz, Keren, Gurken and Vein have been identified for drosophila EGF receptors, called DER. Spitz (SPI) is the major ligand and is involved in most situations where the pathway is activated. Keren plays a minor, redundant role, while Gurken is used exclusively during oogenesis. These ligands are produced as inactive transmembrane precursors, which are retained in the endoplasmic reticulum and needed to processed by the chaperone protein Star. Processed ligands are directed into another compartment where they encounter Rhomboid (RHO) serine proteases, which cleave the ligand precursors within the transmembrane domain to release the active, secreted ligand form. RHO also cleaves and inactivates Star, attenuating the level of cleaved ligand that is produced. The fourth ligand, Vein, is produced as a secreted molecule, which is a weaker activating ligand used either to enhance signalling by other ligands or in specific situations such as muscle patterning. Binding of ligands to DER leads to dimerization and triggering of the canonical DRK/SOS/RAS/RAF/DSOR1/Rolled pathway. DRK (SH2-domain-containing protein) recruits SOS (Son of sevenless, a guanine nucleotide exchange factor) to catalyze the exchange of RAS bound GDP for GTP exchange, thereby activating RAS. RAS then promotes the activation of RAF, leading to DSOR1 activation, and eventually to Rolled (RL) activation. RL inactivates transcriptional co-repressors, such as Aop, and activates transcription factors, such as Pointed (PNT) ([1],[2]). The transcriptional activator PNT is a the major effector of the pathway. The protein Anterior open (AOP) is a constitutive repressor, which competes for PNT binding sites and can be removed from the nucleus and degraded upon phosphorylation by MAP kinases. AOS (Argos), STY (Sprouty) and KEK (Kekkon) are inducible repressive elements involved in negative feedbacks. AOS is a secreted molecule, which sequesters the ligand SPI (Spitz). STY acts downstream of DER, but upstream of RAS and RAF, by recruiting GAP1 and blocking the ability of DRK to bind to its positive effector. KEK is a transmembrane protein forming a non-functional heterodimer with the receptor. Constitutively expressed, CBL (E3 ligase) modulates DER signalling by recognizing activated, internalized receptor molecules and inducing their ubiquitination and degradation. CBL may also enhance the endocytosis of DER, following ligand binding. Modulation of DER signalling by CBL has been reported only in the follicle cells, which receive the Gurken signal from the oocyte ([3], [4], [5], [6]). Our logical model represents a cell receiving different combinations of ligands binding (SPI or Vein or both) and express/receive different levels of inhibitory inputs (Aos, Sty, Cbl, Kek). The signalling pathway is characterized by no signalling, medium or high signalling process designed by multi-valued nodes. We consider five main wild-type cellular situations: i. Cells secreting ligands but lacking Der activation (inhibition of Der), leading to no signalling. ii. Cells receiving medium signal with SPI expressed at level 1 and/or Vein expressed also at level 1, leading to medium signalling. iii. Cells receiving SPI at level of expression 1 (and/or Vein expressed at level 1) and in presence of an inhibitor (e.g. STY, AOS, or KEK), leading to no signalling. iv. Cells receiving SPI at level of expression 2 in the absence of inhibitors, leading to high signalling. v. Cells receiving SPI at level of expression 2 (and/or Vein expressed at level 1) in presence of an inhibitor (e.g. STY, AOS, or KEK,...), leading only to medium signalling.


References

Curation
Submitter: 
Abibatou MBODJ and Denis THIEFFRY

Drosophila Dpp Signalling pathway

Summary: 

Drosophila DPP (TGF-beta homolog) signalling pathway is triggered by ligand-induced formation of heterotetrameric complexes consisting of two type II receptors and two type I receptors with intrinsic serine/threonine kinase activity. The type I receptor (SAX or TKV) is phosphorylated by the constitutively active type II receptor kinase (Punt). Consequently, the complex becomes active and phosphorylates the receptor-regulated Smads (R-Smads). Phosphorylated R-Smads (MAD and Smox) form complexes with a common-mediator Smad (Medea) and translocate into the nucleus, where they regulate the transcription of target genes in co-operation with other transcription factors (nejire, schnurri). DPP is a morphogen, i.e. a molecule distributed in a concentration gradient that elicits different cell fates as a function of its concentration, thereby organizing a series of cell types in a defined spatial array. In response to DPP gradient, cells adopt different fates. The establishment of dpp gradient involves the proteins SOG and TSG. These proteins together capture the DPP ligand and prevent its binding to the receptor (Punt). The heteromeric complex (SOG, DPP, TSG) then release the DPP ligand, a process involving the cleavage of SOG by Tolloid (a metalloprotease). Other TGF-beta signals, Glass-bottom-boa (GBB) and Screw (SCW), help DPP to potentiate cells to respond. SCW and GBB are never expressed together in the same region and affect different cells during: i) early D/V patterning of the embryo and specification/differentiation of dorsal cells (if there is no screw, dpp alone is unable to establish the D/V pattern and embryo lack amnioserosa); ii) the development of adult structures such as the wing. GBB or SCW form heterodimeric complexes with DPP. These heterodimers can only signal through TKV, while SCW/SCW and GBB/GBB signals trough SAX, and DPP/DPP trough TKV and SAX. To model DPP signalling and the formation of the gradient, we have considered three different levels for the TKV receptor (0, 1, 2) and the MADMED effector (0, 1, 2). The regulatory graph also accounts for the potentiation of responding cells due to association of DPP and SCW, or of DPP and GBB. Activated by MADMED, DAD is a pathway inhibitor that can modulate the pathway activity from high to low signalling. DAD works by abrogating the phosphorylation of the MADMED complex by TKV or SAX, thus involving a negative circuit between DAD and the MADMED complex. In addition, BRK another inhibitor of the DPP pathway can block the transcription of dad. Our model reproduces the formation of the DPP signalling gradient and accounts for the role of the heterodimers signalling in cell potentiation. To simulate DPP signalling, we start from an initial state corresponding to non differentiated cell, that can receives high or low level of DPP signal. The use of ternary nodes enables us to account for differential effects of different DPP levels (gradient). The cells receiving high level expression display the hetero-dimers SCW/DPP or GBB/DPP and correspond to Tld expression area, which promotes DPP gradient formation. In presence of medium DPP, TSG and SOG but no TLD are initially needed to capture homo- or hetero-dimer, diminishing pathway signalling intensity (expression level 1 for TKV and MADMED). In presence of high pathway signalling, two situations occur: i) in cells potentiated by SCW: a sequestering complex (SOG/TSG/ DPP/SCW) will release the signalling molecule upon TLD clivage, in addition to normal DPP signalling. This leads to a higher signal transduction. ii) in cells potentiated by GBB, the situation is similar but involve a different heterodimer (GBB/DPP). These situations correspond to two different stable states with high TKV and MADMED (level 2), denoting that more receptors are required to enable a higher level of nuclear MADMED. We consider five different initial states: i) the first one corresponds to the absence of signalling, i.e. absence of DPP; ii) the second one corresponds to medium signalling, characterized by the presence of Dpp at level 1 and of SCW; iii) the third one corresponds to medium signalling, characterized by the presence of Dpp at level 1 and of GBB); iv) the fourth one corresponds to the presence of DPP at level 2 and of SCW; v) the last one corresponds to the presence of DPP at level 2 and of GBB. These set of initial states enable the simulation of five situations. No signalling, two medium and two high signalling that characterize the behavior of the pathway. The stable state obtained with the no signalling simulation shows the absence of binding of the ligands to the receptors TKV and Punt (level of expression 0) and the non activation of target nodes. These medium signals simulations in presence of DPP, show the activation of the receptors (level of expression 1) and subsequent signalling cascade leading to the activation of pathway's targets. These medium signal are defined by the level of expression 1 for DPP, MADMED and TKV while in the high signalling sets, these nodes are expressed at level 2. The node Tkv is multi-valued because the high signalling is characterized by the binding of hetero dimers (DPP/SCW or DPP/GBB) signalling through TKV. Note that GBB and SCW don't have the same expression pattern. For more details on Dpp signalling pathway regulation see [1]; [2]; [3]; [4]; [5].


References

Curation
Submitter: 
Abibatou MBODJ & Denis THIEFFRY
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