Cell-matrix interactions: Structure-activity relationships in integrins.

Cells exist in a highly dynamic extracellular milieu consisting of complex chemicals and mechanical stress signals to which cells must continuously adjust and in turn moderate. In metazoa, the task of integrating these mechanochemical cues across the plasma membrane is divalent-cation-dependent and is mediated by integrins, αβ heterodimeric type I membrane receptors. Integrins are normally expressed in a low affinity state, but rapidly and reversibly switch into high affinity by agonists, which act on the integrin cytoplasmic tails to modify their affinity to extracellular ligands (so-called inside-out activation). Ligands bind activate integrins eliciting classic "outside-in" signals that regulate every aspect of cell function. We have identified a human disease, leukocyte adhesion deficiency, in which a sub-group of integrins, b2 integrins, is lacking. The affected patients suffer from life-threatening bacterial infections. Loss of other integrins causes bleeding diathesis or organ malformations. Improper activation of integrins on the other hand is associated with common inflammatory and metabolic disorders including atherosclerosis, diabetes, and cancer metastasis. A major effort in our laboratory is to understand the structural basis of integrin activation and signaling using biochemical, structural and animal models. A potential outcome is the discovery of small molecule antagonists to treat common diseases linked to integrin dysfunction.

Autosomal Dominant Polycystic Kidney Disease

ADPKD is the most common monogenic disease in humans, caused by dysregulation in diameter of tubular structure including kidney tubules and blood vessels leading chronically to loss of renal function or cutely to cerebral hemorrhage due to ruptured vascular cysts. We have generated a mouse KO of ADPKD and demonstrated that one of the two defective genes, PKD2, encodes a TRP-like calcium channel, which is stabilized by the product of the second gene, PKD1. We have identified a transcriptional modulator of PKD1, which causes pronephric cysts when knocked down in zebrafish. Biochemical and cell biology approaches are being used to elucidate the pathway linking this modulator to cystogenesis in zebrafish and mouse models. Other work attempts to elucidate the signaling pathways involved in determining tube diameter.

This is a new area of investigation in my laboratory, driven initially by serendipitous findings I made while pursuing aspects related to integrins. We found that a zinc finger transcription factor, which regulates ab2 integrin in mature leukocytes, appears to regulate developmental fate of hemangioblasts, the precursors of hematopoietic and vascular stem cells. Work is ongoing to define how each lineage is regulated by this factor at the transcriptional level and the interacting proteins involved using embryonic stem cell/embryoid body cultures, siRNA, and zebrafish and conditional mouse KO models.


  1. Michishita M, Videm V, Arnaout MA. 1993.A novel divalent cation-binding site in the A- domain of the beta 2 integrin CR3 (CD11b/CD18) is essential for ligand binding.Cell. 72: 857.
  2. Lee JO, Rieu P, Arnaout MA (Corresp. author), Liddington R. 1995.Crystal structure of the A domain of the alpha subunit of integrin CR3 (CD11b/CD18).Cell. 80:631.
  3. Kim K, Drummond I, Ibraghimov-Beskrovnaya O, Klinger K, Arnaout MA. 2000.Polycystin 1 is required for the structural integrity of blood vessels.Proc. Natl. Acad. Sci. USA. 97; 1731.
  4. Gonzalez-Perrett S, Kim K, Ibarra C, Damiano AE, Zotta E, Batelli M, Harris PC, Reisin IL, Arnaout MA (Corresp. Author) and Cantiello HF. 2000.Polycystin-2, the protein mutated in autosomal dominant Polycystic Kidney Disease (ADPKD), is a Ca2+-permeable non-selective cation channel.Proc. Natl Acad. Sci. USA. 98; 1182.
  5. Xiong JP, Stehle T, Diefenbach B, Zhang R, Dunker R, Scott DL, Joachimiak A, Goodman SL, and Arnaout MA. 2001.Crystal structure of the extracellular segment of integrin alphaVbeta3.Science. Oct 12; 294(5541):339.
  6. Xiong JP, Stehle T, Zhang R, Dunker R, Joachimiak A, Frech M, Goodman SL, and Arnaout MA. 2002.Crystal structure of the extracellular domain of integrin alphaVbeta3in complex with an Arg-Gly-Asp Ligand.Science. Apr 5; 296(5565): 151-155, 2002.
  7. Alonso J, Essafi M, Xiong JP, Stehle T, and Arnaout MA. 2002.Does the integrin alphaA domain act as a ligand for its betaA domain?Current Biology. 12: R340.
  8. Adair BD, Xiong JP, Maddock C, Goodman SL, Arnaout MA (co-Corresp. Author), Yeager M. 2005.Three dimensional EM structure of the ectodomain of integrin alphaVbeta3 in a complex with fibronectin.J. Cell Biol. 168(7): 1109.
  9. Li X, Xiong JW, Shelley CS, Park H, Arnaout MA. 2006.The transcription factor ZBP-89 controls generation of the hematopoietic lineage in zebrafish and mouse embryonic stem cells.Development. 133(18): 3641.
  10. Xiong JP, Mahalingham B, Alonso JL, Borelli LA, Riu X, Zhang, Anand S, Hyman BT, Rysiok T, Muller-Pompalla D, Goodman SL, and Arnaout MA. 2009.Crystal structure of the complete integrin alphaVbeta3 ectodomain plus an alpha/beta transmembrane fragment.J Cell Biol. 186(4): 589.
  11. Arnaout, MA. 2010.Autosomal Dominant Polycystic Kidney Disease.In Encyclopedia of the Life Sciences. 2010, John Wiley & Sons, Ltd, UK. DOI: 10.1002/9780470015902.a0006010.pub2
  12. Mahalingam B, Ajroud K, Alonso JL, Anand S, Adair B, Horenstein  AL, Malavasi F, Xiong, JP, and Arnaout, MA.Stable coordination of the inhibitory Ca2+ ion at the metal-ion-dependent-adhesion site in integrin CD11b/CD18 by antibody-derived ligand aspartate: Implications for integrin regulation and structure-based drug design.J. Immunol. 2011. 187; 6393. 

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