title: Recent advances in the understanding of the molecular mechanisms regulating platelet integrin αIIbβ3 activation.
abstract: Integrins are allosteric cell adhesion receptors that cycle from a low to a high affinity ligand binding state, a complex process of receptor activation that is of particular importance in blood cells such as platelets or leukocytes. Here we highlight recent progress in the understanding of the molecular pathways that regulate integrin activation in platelets and leukocytes, with a special focus on the structural changes in platelet integrin αIIbβ3 brought about by key intracellular proteins, namely talin and kindlins, that are of crucial importance in the regulation of integrin function. Evidence that the small GTPase Rap1 and its guanine exchange factor CalDAG-GEF1, together with RIAM, a Rap1GTP adaptor protein, promote the interaction of talin with the integrin β subunit, has greatly contributed to fill the gap in our understanding of the signaling pathway from G-coupled agonist receptors and their phospholipase C-dependant second messengers, to integrin activation. Studies of patients with the rare blood cell disorder LAD-III have contributed to the identification of kindlins as new co-regulators of the talin-dependent integrin activation process in platelets and leukocytes, underlining the relevance for the in-depth investigation of patients with rare genetic blood cell disorders.
authors.affiliation: Sino-French Research Center for Life Sciences and Genomics (CNRS/LIA-124), Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Tao
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Xi
authors.forename: Nelly
authors.initials: N
authors.lastname: Kieffer
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion; D003599:Cytoskeleton / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D016608:Talin / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011994:Recombinant Proteins; D016608:Talin