Kindlin supports platelet integrin αIIbβ3 activation by interacting with paxillin. J Cell Sci 2017 Nov 01;130(21):3764-3775
Date
09/29/2017Pubmed ID
28954813Pubmed Central ID
PMC6040092DOI
10.1242/jcs.205641Scopus ID
2-s2.0-85032841608 (requires institutional sign-in at Scopus site) 47 CitationsAbstract
Kindlins play an important role in supporting integrin activation by cooperating with talin; however, the mechanistic details remain unclear. Here, we show that kindlins interacted directly with paxillin and that this interaction could support integrin αIIbβ3 activation. An exposed loop in the N-terminal F0 subdomain of kindlins was involved in mediating the interaction. Disruption of kindlin binding to paxillin by structure-based mutations significantly impaired the function of kindlins in supporting integrin αIIbβ3 activation. Both kindlin and talin were required for paxillin to enhance integrin activation. Interestingly, a direct interaction between paxillin and the talin head domain was also detectable. Mechanistically, paxillin, together with kindlin, was able to promote the binding of the talin head domain to integrin, suggesting that paxillin complexes with kindlin and talin to strengthen integrin activation. Specifically, we observed that crosstalk between kindlin-3 and the paxillin family in mouse platelets was involved in supporting integrin αIIbβ3 activation and in vivo platelet thrombus formation. Taken together, our findings uncover a novel mechanism by which kindlin supports integrin αIIbβ3 activation, which might be beneficial for developing safer anti-thrombotic therapies.
Author List
Gao J, Huang M, Lai J, Mao K, Sun P, Cao Z, Hu Y, Zhang Y, Schulte ML, Jin C, Wang J, White GC, Xu Z, Ma YQAuthor
Gilbert C. White MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Amino Acid SequenceAnimals
Binding Sites
Blood Platelets
Gene Expression
Gene Expression Regulation
Humans
Membrane Proteins
Mice
Mutation
Neoplasm Proteins
Paxillin
Platelet Activation
Platelet Glycoprotein GPIIb-IIIa Complex
Protein Binding
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Interaction Domains and Motifs
Sequence Alignment
Sequence Homology, Amino Acid
Signal Transduction
Talin
Thrombosis
