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• Author/Creator:Harburger, David Steven.
  
• Title:Structure/function analysis of the kindlin family proteins [electronic resource].
  
• ISBN:9781124088051
  
• Physical Description:1 online resource (158 p.)
  
• Links:Online thesis
  

• Yale Holdings

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  • Location:Yale Internet Resource
    Information about Off Campus Access
    
    
  • Call Number: None
    
  • Status:No information available 
  • Notes: Online resource
    

   
• Local Notes:Access is available to the Yale community.
  
• Notes:Source: Dissertation Abstracts International, Volume: 71-07, Section: B, page: 4060.
  Adviser: David A. Calderwood.
  
• Access and use:Access restricted by licensing agreement.
• Summary:Integrins are a major family of cell surface-adhesion receptors formed by a heterodimeric complex of two transmembrane proteins, the alpha and beta subunits. Proper integrin function is important for many cellular processes, such as adhesion, migration, spreading, survival and regulation of transcription. Integrin activation, the conversion of integrins from low to high affinity, occurs in response to intracellular signals that act on the short cytoplasmic tails of integrin beta subunits. Talin binding to integrin beta tails provides one key activation signal, but additional factors are likely to cooperate with talin to regulate integrin activation.
  Here we report on kindlin interactions with beta integrin tails and describe the effect of kindlin expression on integrin activation. We biochemically map regions within the FERM domain of kindlin-1 and -2 and in the distal portion of integrins beta1 and beta3 tails as required for direct binding. Using fluorescence-activated cell sorting we further show that kindlin-1 and -2 are capable of enhancing talin-mediated activation of beta3, but not beta1, integrins when co-expressed with talin in cell culture. We suggest that kindlins are adaptor proteins that regulate integrin activation, that kindlin expression levels determine their effects, and that kindlins may exert integrin-specific effects.
  To further examine kindlin interactions, we investigated the N-terminal portion of kindlin-1. We report that kindlins contain an FO region on their N terminus that is structurally similar to that of talin FO and is required for both integrin activation and targeting of kindlin to focal adhesions. This information is valuable for directing future studies of kindlin intra- and inter-molecular interactions.
  We also investigate the filamin-binding and LIM domain-containing protein migfilin as an important factor in integrin signaling. We first show that the N terminus of migfilin binds directly to the immunoglobulin-like repeat 21 of filamin. Furthermore, we show that migfilin can compete with integrin tails for access to filamin, suggesting a mode of regulating integrin activation. We identify the LIM2 region of migfilin as required for targeting to focal adhesions and present progress towards biochemically examining a migfilin-kindlin interaction. Collectively, this dissertation provides insights towards kindlin-mediated regulation of integrin signaling.
  
• In_:Dissertation Abstracts International 71-07B.
  
• Format:Book
• Thesis note:Thesis (Ph.D.)--Yale University, 2010.
  
• Also listed under:Yale University.