Disintegrins:integrin selective ligands which activate integrin-coupled signaling and modulate leukocyte functions Authors C.Bajra-Fidalgo,A.L.j.coelho,R.Saldanha-Gama, E.Helal-Neto,and M.S.de Freitas

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Disintegrinsintegrin selective ligands which
activate integrin-coupled signaling and modulate
leukocyte functionsAuthorsC.Bajra-Fidalgo,A.L.j
.coelho,R.Saldanha-Gama, E.Helal-Neto,and M.S.de
Freitas

• Presented By
• P.Vipula

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Background

• Integrins are a large family of heterodimeric
  glycoproteins that attach cells to ECM proteins
  of the basement or to ligands on other cells ,
  with out which cell migration is not possible.
• Integrins are the adhesion molecules. As they
  integrate the function of cell with the outside
  world they got that name.
• The interaction between integrins and ECM
  regulates cell survival , cell growth, gene
  expression and function.
• ß-Barrel shaped integrins are made of 120-170 KDa
  of a subunit and 90-100 KDa of ß-subunit.

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Background contin.

• In mammals nearly 18-a subunits and 8-ß subunits
  were cloned leading to 24 aß Heterodimers.
• Integrins are Bidirectional signaling molecules.
  
• Extracellular matrix molecules Fibronectin ,
  laminins.
• Intracellular ligands talin, a actinin.
• Integrins are linked to structural proteins like
  Vinculin, actin microfilaments,FAKs etc.

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Integrin Structure

• Each subunit crosses the transmembrane once,
  with each polypeptide in the extracellular space
  and short cytoplasmic domains .
• Through extracellular domain integrins bind to
  ECM.
• a and ß are non covalently bound.
• a subunit has specificity of ligand binding.

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Types Of ß-2 Integrins
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Integrins and Signal Transduction

• Integrins play an important role not only in
  structure architecture of tissues, but also for
  signal transduction leading to regulation of
  functions in cell.
• Focal adhesion kinase (FAK) becomes tyrosine
  phosphorylated during integrin - mediated cell
  adhesion.
• FAK is a non-receptor tyrosine kinase interacting
  with C- src, PI3-K,Rho GTPase,Grb-2 and p130 CAS
  .
• FAK-generated signaling is involved in cell
  survival and essential for development.

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• FAK can be phosphorylated on different tyrosine
  residues like tyr397 conforms to consensus
  binding for SH-2 domains for C-Src and p85
  regulatory subunit of PI3-K and activates the
  PI3-K.
• Integrins-mediated cell adhesion can activate
  MAPK including Erk-1, c-Jun kinase, and p38 which
  leads to transcriptional regulation of certain
  genes cell growth, differentiation and
  apoptosis.
• I.M.C.A also stimulates Rho family members
  including RhoA,Rac1, CDC42 and bring Actin
  Polymerization.
• Activation of Rho family is important for actin
  rearrangement.

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• Activated FAK is associated with PI3-K through
  Tyr397 residue, Phosphorylating the P85 subunit
  and activating the PI3-K.
• PI3-K-effector proteins are involved in
  regulation of integrin mediated leukocyte
  migration and immune cell proliferation,
  differentiation and survival.
• Regulation of catalytic activity of FAK signaling
  site specific dephosphorylation of tyrosine
  residues.

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Disintegrins

• A family of Cysteine rich peptide with RGD motif
  .This tripeptide sequence is the cell attachment
  site recognized by integrins.
• Through RGD motifs Disintegrins bind to integrins
  inhibiting integrin related functions.
• Integrin inhibitory proteins were first
  discovered in snake venom, and are potent
  antagonists of platelet aggregation and integrins
  cellular adhesive functions.
• In snake venom disintegrins peptides had other
  active sequences like KGD,MVD,MLD,VGD,ECD,or MDG
  in integrin motifs.
• Different disintegrins are eristostatin,
  echistatin,kistrin, and flavoridin are able to
  bind to aIIbß3 potent inhibitors of platelet
  aggregation and tumor cell metastasis.

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Leukocytes and integrin signaling

• Integrins are dominant family of cell adhesion
  receptors involved in leukocyte interactions with
  endothelium and ECM .
• Integrin signaling pathways mediate important
  functions in leukocytes, including migration,
  spreading, activation of the respiratory burst,
  complement binding, cell adhesion, cytokines and
  chemokine expression, and apoptosis .
• During inflammation, neutrophils roll along the
  endothelial wall of postcapillary venules
  producing different inflammatory signals.
• FAK, recruits signaling proteins-PI3-K and
  signaling via PI3K regulates the migration and
  immune T-cell proliferation ,survival and
  differentiation.

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• Triggering of several intracellular signaling
  pathways linked to FAK and PI3-K activation
  includes Ras/Raf/MAPK pathway which can control
  various neutrophil functions.
• Once leukocytes are guided to sites of infection,
  inflammation ,or antigen presentation, integrins
  can participate in the initiation, maintainence,
  or termination of the immune and inflammatory
  responses.
• Disintegrins like Jarastatin(JT) were able to
  bind to aMß2 integrin on neutrophils and inhibit
  their migration.
• Disintegrins are tools that can be used to
  understand the cellular events mediated by
  adhesion molecules.

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Conclusions

• In FAK deficient mice developmental defect
  associated with impairment of cell migration and
  enhancement of cell adhesion.
• Integrin mediated c-Jun kinase activation is
  dependent on FAK and is involved in cell cycle
  progression and cell spreading and cell survival.
• Activation of p38 MAPK by integrins regulate
  collagen gene expression and cell motility.
• Integrin- mediated cell adhesion also stimulates
  RHO family members including RhoA, Rac1, and
  CDC42.
• Disintegrins ,ligands of aIIbß3 is a potent
  inhibitors of platelet aggregation and tumor cell
  metastasis, and ligands of a5 ß1 and avß3
  inhibits angiogenesis and induce apoptosis in
  cells.

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• ACKNOWLEDGEMENTS
• Dr. RINEHART
• BIOLOGY DEPARTMENT, WKU.
• PRABHAVATHI and SANKARA REDDY PETLURU.