Fibrin complement receptor 3 signaling (Homo sapiens)

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567, 118, 1036461212666NucleusMyD88-dependentDegradationCytoskeletal rearrangementLigand-independentsignalingdsRNAFibrin DegradationProductsTIRAPLPSAKT1FibrintPAIRAK1NF-kBFcRgSYKCD14RHOACXCL10DAP12RAPLCXCL3PlasminogenMYD88TRIFIL6TLR3IFNB1PI3KIKBKBCBL-BBlood Clotting CascadeTRAF6PPlasminIRAK4MD2LBPTLR4SRCTRAFIRF3P6CD11bCD18Phagocytosis1, 2TRIFMYD88PP12TNFSYKIRF3PCCL25NF-kBCHUKIKBKGPI3KMyD88-independentFibrinogenIRAK2IL12BNOS2


Description

The plasma protein fibrinogen, a key component of the blood coagulation process, has been identified as an early molecular factor triggering neuroinflammation (see bibliography). Upon fibrinogen extravasation across leaky vessels (i.e., break down of the blood-brain barrier), fibrinogen is converted by thrombin to insoluble fibrin. Based on published studies, this signaling pathway highlights fibrin as a CD11b/CD18 (complement receptor; CR3) integrin receptor ligand that regulates innate immunity. Fibrin activates central nervous system (CNS) resident microglia and peripheral (bone marrow derived) macrophages via CR3, leading to intracellular kinase signaling activation including PI3K, AKT1 and RhoA activity that regulates phagocytosis; and NF-κB translocation to the nucleus that transcriptionally regulates proinflammatory cytokines and chemokines that recruit T-cells and macrophages. Interestingly, canonical LPS-TLR4 activation of innate immune cells is known to trans-activate CD11b to negatively regulate TLR4 activation in a ligand-independent mechanism.

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Ontology Terms

 

Bibliography

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  1. Caron E, Hall A; ''Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases.''; Science, 1998 PubMed Europe PMC Scholia
  2. Ugarova TP, Lishko VK, Podolnikova NP, Okumura N, Merkulov SM, Yakubenko VP, Yee VC, Lord ST, Haas TA; ''Sequence gamma 377-395(P2), but not gamma 190-202(P1), is the binding sitefor the alpha MI-domain of integrin alpha M beta 2 in the gamma C-domain of fibrinogen.''; Biochemistry, 2003 PubMed Europe PMC Scholia
  3. Flick MJ, Du X, Witte DP, Jirousková M, Soloviev DA, Busuttil SJ, Plow EF, Degen JL; ''Leukocyte engagement of fibrin(ogen) via the integrin receptor alphaMbeta2/Mac-1 is critical for host inflammatory response in vivo.''; J Clin Invest, 2004 PubMed Europe PMC Scholia
  4. Stephens L, Ellson C, Hawkins P; ''Roles of PI3Ks in leukocyte chemotaxis and phagocytosis.''; Curr Opin Cell Biol, 2002 PubMed Europe PMC Scholia
  5. Means TK, Luster AD; ''Integrins limit the Toll.''; Nat Immunol, 2010 PubMed Europe PMC Scholia
  6. Ryu JK, Petersen MA, Murray SG, Baeten KM, Meyer-Franke A, Chan JP, Vagena E, Bedard C, Machado MR, Rios Coronado PE, Prod'homme T, Charo IF, Lassmann H, Degen JL, Zamvil SS, Akassoglou K; ''Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation.''; Nat Commun, 2015 PubMed Europe PMC Scholia
  7. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B; ''Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene.''; Science, 1998 PubMed Europe PMC Scholia
  8. Han C, Jin J, Xu S, Liu H, Li N, Cao X; ''Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b.''; Nat Immunol, 2010 PubMed Europe PMC Scholia
  9. Adams RA, Bauer J, Flick MJ, Sikorski SL, Nuriel T, Lassmann H, Degen JL, Akassoglou K; ''The fibrin-derived gamma377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease.''; J Exp Med, 2007 PubMed Europe PMC Scholia
  10. Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO; ''The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex.''; Nature, 2009 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
129747view01:55, 22 May 2024EweitzModified title
127352view18:35, 20 September 2023Khanspersupdated phospho sites
120387view08:12, 30 November 2021EgonwMade another pathway clickable
119690view21:57, 29 July 2021Khanspersupdate xrefs
118430view14:29, 27 May 2021Mkutmonremoved unused reference
117109view21:33, 17 May 2021EweitzModified title
106418view22:00, 28 August 2019KhanspersModified description
105597view04:48, 10 August 2019KhanspersModified description
105118view18:38, 8 July 2019Khanspersupdated fibrinogen xrefs
103640view23:28, 22 March 2019AlexanderPicoAdded ID for PI3K
98484view17:31, 11 September 2018Khanspersfixed broken literature reference
96449view09:27, 15 March 2018EgonwReplaced a secondary ChEBI identifier with a primary identifier.
95528view17:24, 20 December 2017Khanspersfixed unconnected
95522view18:16, 19 December 2017Khanspersupdated xref for PI3K
95521view17:55, 19 December 2017KhanspersOntology Term : 'coagulation cascade pathway' added !
95520view17:53, 19 December 2017KhanspersOntology Term : 'classical complement pathway' added !
95519view17:52, 19 December 2017KhanspersOntology Term : 'inflammatory response pathway' added !
95518view17:51, 19 December 2017KhanspersOntology Term : 'microglial cell' added !
95517view17:50, 19 December 2017KhanspersOntology Term : 'macrophage' added !
95515view02:24, 19 December 2017AkassoglouModified description
95514view02:23, 19 December 2017AkassoglouModified description
95513view02:23, 19 December 2017AkassoglouModified title
94852view23:11, 9 October 2017Khansperslayout update
94302view05:18, 1 September 2017KhanspersOntology Term : 'microglial cell' added !
94278view18:43, 30 August 2017AndrewmendiolaModified description
93729view23:57, 15 August 2017KhanspersNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
AKT1GeneProductENSG00000142208 (Ensembl)
Blood Clotting CascadePathwayWP272 (WikiPathways)
CBL-BProteinE9PHA9 (Uniprot-TrEMBL)
CCL2GeneProductENSG00000108691 (Ensembl)
CD11bGeneProductENSG00000169896 (Ensembl)
CD14GeneProductENSG00000170458 (Ensembl)
CD18GeneProductENSG00000160255 (Ensembl)
CHUKGeneProductENSG00000213341 (Ensembl)
CXCL10GeneProductENSG00000169245 (Ensembl)
CXCL3GeneProductENSG00000163734 (Ensembl)
DAP12GeneProductENSG00000011600 (Ensembl)
FcRgGeneProduct
FibrinMetaboliteCHEBI:5054 (ChEBI)
FibrinogenGeneProduct
IFNB1GeneProductENSG00000171855 (Ensembl)
IKBKBGeneProductENSG00000104365 (Ensembl)
IKBKGGeneProductENSG00000269335 (Ensembl)
IL12BGeneProductENSG00000113302 (Ensembl)
IL6GeneProductENSG00000136244 (Ensembl)
IRAK1GeneProductENSG00000184216 (Ensembl)
IRAK2GeneProductENSG00000134070 (Ensembl)
IRAK4GeneProductENSG00000198001 (Ensembl)
IRF3GeneProductENSG00000126456 (Ensembl)
LBPGeneProductENSG00000129988 (Ensembl)
LPSMetaboliteCHEBI:14520 (ChEBI)
MD2GeneProductENSG00000154589 (Ensembl)
MYD88GeneProductENSG00000172936 (Ensembl)
NF-kBGeneProductENSG00000109320 (Ensembl)
NF-kBGeneProduct
NOS2GeneProductENSG00000007171 (Ensembl)
PI3KGeneProduct
PlasminGeneProductENSG00000122194 (Ensembl)
PlasminogenGeneProductENSG00000122194 (Ensembl)
RAPLGeneProductENSG00000266094 (Ensembl)
RHOAGeneProductENSG00000067560 (Ensembl)
SRCGeneProductENSG00000197122 (Ensembl)
SYKGeneProductENSG00000165025 (Ensembl)
TIRAPGeneProductENSG00000150455 (Ensembl)
TLR3GeneProductENSG00000164342 (Ensembl)
TLR4GeneProductENSG00000136869 (Ensembl)
TNFGeneProductENSG00000232810 (Ensembl)
TRAF6GeneProductENSG00000175104 (Ensembl)
TRAFGeneProductENSG00000243414 (Ensembl)
TRIFGeneProductENSG00000127666 (Ensembl)
tPAGeneProductENSG00000104368 (Ensembl)

Annotated Interactions

No annotated interactions

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