Page 1909 - Williams Hematology ( PDFDrive )

1884 Part XII: Hemostasis and Thrombosis Chapter 112: Platelet Morphology, Biochemistry, and Function 1885

related integrin α β , are in a bent conformation when inactive and an of integrin α β on platelets. 1741 Mutations in kindlin-3 have been
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extended conformation when activated. 149,843,844 The activation state of described in patients with leukocyte adhesion deficiency-III, which is
integrin α β is controlled by the cytoplasmic domains of this integ- characterized by abnormalities in leukocyte and platelet integrin acti-
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rin in concert with specific intracellular binding proteins. Thus, under vation and function (Chap. 121). 1742–1745 In fact, the bleeding symptoms
basal conditions, interactions between the cytoplasmic domains of inte- are even more severe than those in Glanzmann thrombasthenia and the
grins α and β maintain the receptor in the resting state. Interrupt- platelet aggregation defects are similar. Mutational analysis also iden-
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ing the interactions between the cytoplasmic domains results in long tified the NXXY motif (Tyr795) and preceding threonine-region in
range conformational changes that convert the extracellular portion kindlin binding to integrin β . 1746 Finally, based on model systems, it has
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of the integrin to an active state. 1724 Interactions between regions of been proposed that α transmembrane and cytoplasmic domains from
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the integrins α and β transmembrane and cytoplasmic domains near adjacent integrin α β receptors may form homodimers and integrin
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the membrane involve upper and lower membrane clasps and a salt β transmembrane and cytoplasmic domains may form homotrimers,
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bridge between acidic and basic amino acid residues of each subunit (see resulting in stabilization of the activated state and clustering of integ-
“Integrin α β ” above). 871,894,1725,1726 Mutations that disrupt these interac- rin α β receptors, 251,1747 but it is not clear that these interactions are
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tions result in integrin α β activation. 871,894,1726 Cytoskeletal restraints favored under biologic conditions. 871,894
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appear to further maintain integrin α β in an inactive conformation, Platelet aggregation is commonly described as progressing through
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because treatment of platelets with low doses of the actin depolymeriz- two phases: an initial reversible aggregation phase, which is often the
ing agents activate the integrin. Upon agonist activation, the binding response observed with low concentrations of agonists, followed by a
243
of the cytoskeletal linking proteins talin and kindlin to integrin β may stronger, irreversible phase. The irreversible phase of aggregation cor-
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play a key role in the conversion of integrin α β , as well as several relates with TXA production and platelet secretion of ADP. Fibrinogen
2
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other integrins, to an active conformation. One model suggests that binding to integrin α β and the platelet–platelet contacts that occur
245
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filamin binding to the β subunit cytoplasmic tail maintains the receptor during the initial phase of aggregation initiate specific signal transduc-
in an inactive state by presenting talin binding. The cytoskeletal adap- tion events, resulting in positive feedback loops that promote irrevers-
ter protein migfilin can displace filamin from the integrin β subunit ible aggregation, maintain secretion, and initiate later events like clot
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and facilitate the binding of talin. Talin itself can exist in a confor- retraction. 291
mation that is either less or more favorable for binding to integrin β at Fibrinogen or VWF binding to the extracellular region of integ-
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multiple sites. The affinity of talin for β integrins increases in response rin α β transmits long-range conformational changes to the integrin
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to PI(4,5)P binding to talin. 1727 PIP may be generated locally from PI cytoplasmic domains, perhaps via a pivot action between the integrin
2
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via the enzyme phosphatidylinositol phosphate kinase type 1γ, which β βA (I-like) and hybrid domains that induce signaling from out-
827
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can bind to talin. 1728,1729 Talin is composed of a Mr 47,000 head domain side the platelet to inside the platelet (outside-in signaling). 876,879 These
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and a Mr 190,000 rod domain. The head contains a “FERM” domain conformational changes, along with integrin clustering, are likely to
named for the proteins four point one (4.1), ezrin, radixin, and moesin, be the basis for outside-in signal transduction through integrin α β ,
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that promotes specific interactions with cytoplasmic regions of multi- perhaps by altering the association of the cytoplasmic domains with one
ple proteins. The F3 region of the FERM domain, which resembles a another and initiating recruitment of proteins with enzymatic activity
phosphotyrosine binding (PTB) domain, 1730 binds sequentially to mem- to the cytoplasmic tails, forming complexes capable of generating sig-
brane distal and proximal regions of integrin β in addition to establish- naling molecules.
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ing electrostatic interactions with the lipid head groups, disrupting its One important signaling molecule that is constitutively associated
interaction with the membrane and integrin α . 244,871,894,896,1730–1734 This with the integrin β cytoplasmic tail is the tyrosine kinase, Src. 1748–1750
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binding site is not available when PI phosphate kinase (PIPK)I is bound Src binds to the C-terminus of the integrin in resting platelets via its
to talin, so presumably any prebound PIPKI would be displaced from SH3 domain independent of its catalytic activity. 1748 This pool of Src in
talin upon talin interaction with integrin β . 3 1735 After talin binding the unstimulated platelets appears to exist in a minimally active state with
reorganization of the transmembrane and intracytoplasmic domains its activity suppressed in part by the Src regulator Csk, which phospho-
disrupt the interaction of integrins α and β and this is transmitted rylates Src at Tyr 529. Platelet adhesion to fibrinogen increases the Src
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to the ectodomain. 871,894,1724 The β cytoplasmic domain can also bind activity associated with integrin α β in part because of the dissocia-
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proteins that connect it to the cytoskeleton such as α-actinin, ICAP1, fil- tion of Csk and subsequent dephosphorylation of Src 529. 1750 Full Src
amin, Src, and skelemin, and so it has been proposed that interactions of activation occurs upon integrin α β clustering and transphosphoryla-
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the integrin β subunit with the actin–myosin contraction apparatus via tion of Src on Tyr 418. Src activation is required for several subsequent
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the cytoskeleton may supply the energy needed to adopt the extended signaling events such as the activation of the tyrosine kinase Syk. Syk,
conformation of integrin α β with the swing out of the of integrin β along with Src, is required for platelet spreading on fibrinogen. 1748 Syk
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hybrid domain away from the of βA (I-like) domain. The rod-like binds to unphosphorylated integrin β via its N-terminus. 1751,1752 Some
250
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region of talin has also been reported to interact with integrin β , 1736 and of these events have now been visualized in living platelets. 1753 Negative
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an unknown region of talin has been reported to interact with integrin regulators of Src activation include PECAM-1, which can recruit the
α . 1737 While these interactions may serve to stabilize or subsequently protein tyrosine phosphatases SHP-1 and SHP-2 via its ITIMs 1749,1754–1757 ;
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cluster the integrin, their exact roles are unknown. carcinoembryonic antigen-related cell adhesion molecule-1, which also
Members of the kindlin family of focal adhesion proteins that possess ITIMs 1758 ; and perhaps G6b-B 1759–1761 and TLT-1. 1166
contain PTB domains serve as integrin activators, 1738–1740 perhaps func- When platelets are aggregated in response to one of multiple ago-
tioning to facilitate talin–integrin interactions. Kindlin-2 binds the nists, the integrin β cytoplasmic domain becomes phosphorylated on
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C-terminus of integrin β in a region containing the conserved TS(752) Tyr. 902,910 Two sites of potential tyrosine phosphorylation exist on the β
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T sequence and NITY(759) motif and acts synergically with talin to pro- cytoplasmic domain and both may be utilized. Several molecules have
mote integrin α β activation in a recombinant expression system. 1738 been identified that bind specifically to the tyrosine-phosphorylated
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Whereas kindlin-2 is widely distributed, kindlin-3 expression is limited cytoplasmic domain of integrin β . A synthetic integrin β cytoplasmic
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to hematopoietic cells, including platelets. Genetic deletion of kindlin-3 domain peptide containing phosphate groups on the two candidate Tyr
902
in mice results in a severe bleeding phenotype and defective activation residues binds to the contractile protein myosin, and this interaction
Kaushansky_chapter 112_p1829-1914.indd 1884 17/09/15 3:30 pm