The Rap1-RIAM-talin axis of integrin activation and blood cell function

Blood

Volumn 128, Issue 4, 2016, Pages 479-487

  Lagarrigue, Frederic ^a   Kim, Chungho ^b   Ginsberg, Mark H ^a  

^a UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

^b Korea University   (South Korea)

Author keywords

[No Author keywords available]

Indexed keywords

BETA INTEGRIN; BINDING PROTEIN; GUANOSINE TRIPHOSPHATASE; GUANOSINE TRIPHOSPHATASE ACTIVATING PROTEIN; INTEGRIN; KINDLIN; PROTEIN; RAP PROTEIN; RAP1 GTP INTERACTING ADAPTER MOLECULE; RAP1 PROTEIN; TALIN; UNCLASSIFIED DRUG; APBB1IP PROTEIN, HUMAN; MEMBRANE PROTEIN; SIGNAL TRANSDUCING ADAPTOR PROTEIN; TELOMERE BINDING PROTEIN; TERF2IP PROTEIN, HUMAN;

ALLOSTERISM; BIOCHEMICAL ANALYSIS; BLOOD CELL; CELL ADHESION; CELL FUNCTION; CELL MEMBRANE; CYTOPLASM; HUMAN; NONHUMAN; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN INDUCTION; PROTEIN PROTEIN INTERACTION; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; CELL MOTION; CYTOLOGY; LEUKOCYTE; METABOLISM; PHYSIOLOGY;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; CELL MOVEMENT; HUMANS; INTEGRINS; LEUKOCYTES; MEMBRANE PROTEINS; PROTEIN DOMAINS; TALIN; TELOMERE-BINDING PROTEINS;

EID: 84987596101     PISSN: 00064971     EISSN: 15280020     Source Type: Journal    
DOI: 10.1182/blood-2015-12-638700     Document Type: Review

References (119)

1. Vestweber D. How leukocytes cross the vascular endothelium. Nat Rev Immunol. 2015;15(11):692-704.
2. Davì G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med. 2007;357(24):2482-2494.
3. Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell. 2002;110(6):673-687.
4. Humphries JD, Byron A, Humphries MJ. Integrin ligands at a glance. J Cell Sci. 2006;119(Pt 19):3901-3903.
5. Hogg N, Patzak I, Willenbrock F. The insider's guide to leukocyte integrin signalling and function. Nat Rev Immunol. 2011;11(6):416-426.
6. Luo BH, Carman CV, Springer TA. Structural basis of integrin regulation and signaling. Annu Rev Immunol. 2007;25:619-647.
7. Bledzka K, Smyth SS, Plow EF. Integrin αIIbβ3: from discovery to efficacious therapeutic target. Circ Res. 2013;112(8):1189-1200.
8. Arnaout MA, Dana N, Gupta SK, Tenen DG, Fathallah DM. Point mutations impairing cell surface expression of the common beta subunit (CD18) in a patient with leukocyte adhesion molecule (Leu-CAM) deficiency. J Clin Invest. 1990;85(3):977-981.
9. Wardlaw AJ, Hibbs ML, Stacker SA, Springer TA. Distinct mutations in two patients with leukocyte adhesion deficiency and their functional correlates. J Exp Med. 1990;172(1):335-345.
10. Buitrago L, Rendon A, Liang Y, et al; ThromboGenomics Consortium. αIIbβ3 variants defined by next-generation sequencing: predicting variants likely to cause Glanzmann thrombasthenia. Proc Natl Acad Sci USA. 2015;112(15):E1898-E1907.
11. Springer TA, Dustin ML. Integrin inside-out signaling and the immunological synapse. Curr Opin Cell Biol. 2012;24(1):107-115.
12. Takagi J, Petre BM, Walz T, Springer TA. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell. 2002;110(5):599-11.
13. Xiong JP, Stehle T, Diefenbach B, et al. Crystal structure of the extracellular segment of integrin alpha Vbeta3. Science. 2001;294(5541):339-345.
14. Shattil SJ, Kim C, Ginsberg MH. The final steps of integrin activation: the end game. Nat Rev Mol Cell Biol. 2010;11(4):288-300.
15. Kim C, Ye F, Ginsberg MH. Regulation of integrin activation. Annu Rev Cell Dev Biol. 2011;27:321-345.
16. Ye F, Hu G, Taylor D, et al. Recreation of the terminal events in physiological integrin activation. J Cell Biol. 2010;188(1):157-173.
17. Ye F, Lagarrigue F, Ginsberg MH. SnapShot: Talin and the modular nature of the integrin adhesome. Cell. 2014;156(6):1340-1341.
18. Nieswandt B, Moser M, Pleines I, et al. Loss of talin1 in platelets abrogates integrin activation, platelet aggregation, and thrombus formation in vitro and in vivo. J Exp Med. 2007;204(13):3113-3118.
19. Petrich BG, Marchese P, Ruggeri ZM, et al. Talin is required for integrin-mediated platelet function in hemostasis and thrombosis. J Exp Med. 2007;204(13):3103-3111.
20. Lefort CT, Rossaint J, Moser M, et al. Distinct roles for talin-1 and kindlin-3 in LFA-1 extension and affinity regulation. Blood. 2012;119(18):4275-4282.
21. Calderwood DA, Zent R, Grant R, Rees DJ, Hynes RO, Ginsberg MH. The Talin head domain binds to integrin beta subunit cytoplasmic tails and regulates integrin activation. J Biol Chem. 1999;274(40):28071-28074.
22. Tadokoro S, Shattil SJ, Eto K, et al. Talin binding to integrin beta tails: a final common step in integrin activation. Science. 2003;302(5642):103-106.
23. Anthis NJ, Wegener KL, Ye F, et al. The structure of an integrin/talin complex reveals the basis of inside-out signal transduction. EMBO J. 2009;28(22):3623-3632.
24. García-Alvarez B, de Pereda JM, Calderwood DA, et al. Structural determinants of integrin recognition by talin. Mol Cell. 2003;11(1):49-58.
25. Wegener KL, Partridge AW, Han J, et al. Structural basis of integrin activation by talin. Cell. 2007;128(1):171-182.
26. Petrich BG, Fogelstrand P, Partridge AW, et al. The antithrombotic potential of selective blockade of talin-dependent integrin alpha IIb beta 3 (platelet GPIIb-IIIa) activation. J Clin Invest. 2007;117(8):2250-2259.
27. Haling JR, Monkley SJ, Critchley DR, Petrich BG. Talin-dependent integrin activation is required for fibrin clot retraction by platelets. Blood. 2011;117(5):1719-1722.
28. Stefanini L, Ye F, Snider AK, et al. A talin mutant that impairs talin-integrin binding in platelets decelerates αIIbβ3 activation without pathological bleeding. Blood. 2014;123(17):2722-2731.
29. Yago T, Petrich BG, Zhang N, et al. Blocking neutrophil integrin activation prevents ischemia-reperfusion injury. J Exp Med. 2015;212(8):1267-1281.
30. Watanabe N, Bodin L, Pandey M, et al. Mechanisms and consequences of agonist-induced talin recruitment to platelet integrin alphaIIbbeta3. J Cell Biol. 2008;181(7):1211-1222.
31. Berger BW, Kulp DW, Span LM, et al. Consensus motif for integrin transmembrane helix association. Proc Natl Acad Sci USA. 2010;107(2):703-708.
32. Hughes PE, Diaz-Gonzalez F, Leong L, et al. Breaking the integrin hinge. A defined structural constraint regulates integrin signaling. J Biol Chem. 1996;271(12):6571-6574.
33. Luo BH, Springer TA, Takagi J. A specific interface between integrin transmembrane helices and affinity for ligand. PLoS Biol. 2004;2(6):e153.
34. Partridge AW, Liu S, Kim S, Bowie JU, Ginsberg MH. Transmembrane domain helix packing stabilizes integrin alphaIIbbeta3 in the low affinity state. J Biol Chem. 2005;280(8):7294-7300.
35. Kim M, Carman CV, Springer TA. Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins. Science. 2003;301(5640):1720-1725.
36. Lau TL, Partridge AW, Ginsberg MH, Ulmer TS. Structure of the integrin beta3 transmembrane segment in phospholipid bicelles and detergent micelles. Biochemistry. 2008;47(13):4008-4016.
37. Lau TL, Kim C, Ginsberg MH, Ulmer TS. The structure of the integrin alphaIIbbeta3 transmembrane complex explains integrin transmembrane signalling. EMBO J. 2009;28(9):1351-1361.
38. Strandberg E, Killian JA. Snorkeling of lysine side chains in transmembrane helices: how easy can it get? FEBS Lett. 2003;544(1-3):69-73.
39. Kim C, Schmidt T, Cho EG, Ye F, Ulmer TS, Ginsberg MH. Basic amino-acid side chains regulate transmembrane integrin signalling. Nature. 2011;481(7380):209-213.
40. Calderwood DA, Yan B, de Pereda JM, et al. The phosphotyrosine binding-like domain of talin activates integrins. J Biol Chem. 2002;277(24):21749-21758.
41. Kalli AC, Campbell ID, Sansom MS. Multiscale simulations suggest a mechanism for integrin inside-out activation. Proc Natl Acad Sci USA. 2011;108(29):11890-11895.
42. Kim C, Ye F, Hu X, Ginsberg MH. Talin activates integrins by altering the topology of the β transmembrane domain. J Cell Biol. 2012;197(5):605-611.
43. Lingwood D, Simons K. Lipid rafts as a membrane-organizing principle. Science. 2010;327(5961):46-50.
44. Leitinger B, Hogg N. The involvement of lipid rafts in the regulation of integrin function. J Cell Sci. 2002;115(Pt 5):963-972.
45. Decker L, ffrench-Constant C. Lipid rafts and integrin activation regulate oligodendrocyte survival. J Neurosci. 2004;24(15):3816-3825.
46. Hamill OP, Martinac B. Molecular basis of mechanotransduction in living cells. Physiol Rev. 2001;81(2):685-740.
47. Anishkin A, Loukin SH, Teng J, Kung C. Feeling the hidden mechanical forces in lipid bilayer is an original sense. Proc Natl Acad Sci USA. 2014;111(22):7898-7905.
48. Berrier C, Pozza A, de Lacroix de Lavalette A, et al. The purified mechanosensitive channel TREK-1 is directly sensitive to membrane tension. J Biol Chem. 2013;288(38):27307-27314.
49. Brohawn SG, Su Z, MacKinnon R. Mechanosensitivity is mediated directly by the lipid membrane in TRAAK and TREK1 K+ channels. Proc Natl Acad Sci USA. 2014;111(9):3614-3619.
50. Cymer F, Veerappan A, Schneider D. Transmembrane helix-helix interactions are modulated by the sequence context and by lipid bilayer properties. Biochim Biophys Acta. 2012;1818(4):963-973.
51. Nomura T, Cranfield CG, Deplazes E, et al. Differential effects of lipids and lyso-lipids on the mechanosensitivity of the mechanosensitive channels MscL and MscS. Proc Natl Acad Sci USA. 2012;109(22):8770-8775.
52. Phillips R, Ursell T, Wiggins P, Sens P. Emerging roles for lipids in shaping membrane-protein function. Nature. 2009;459(7245):379-385.
53. Katsumi A, Naoe T, Matsushita T, Kaibuchi K, Schwartz MA. Integrin activation and matrix binding mediate cellular responses to mechanical stretch. J Biol Chem. 2005;280(17):16546-16549.
54. Li R, Mitra N, Gratkowski H, et al. Activation of integrin alphaIIbbeta3 by modulation of transmembrane helix associations. Science. 2003;300(5620):795-798.
55. Yin H, Litvinov RI, Vilaire G, et al. Activation of platelet alphaIIbbeta3 by an exogenous peptide corresponding to the transmembrane domain of alphaIIb. J Biol Chem. 2006;281(48):36732-36741.
56. Ye F, Kim SJ, Kim C. Intermolecular transmembrane domain interactions activate integrin αIIbβ3. J Biol Chem. 2014;289(26):18507-18513.
57. Carman CV, Springer TA. Integrin avidity regulation: are changes in affinity and conformation underemphasized? Curr Opin Cell Biol. 2003;15(5):547-556.
58. Karaköse E, Schiller HB, Fässler R. The kindlins at a glance. J Cell Sci. 2010;123(Pt 14):2353-2356.
59. Plow EF, Qin J, Byzova T. Kindling the flame of integrin activation and function with kindlins. Curr Opin Hematol. 2009;16(5):323-328.
60. Ussar S, Moser M, Widmaier M, et al. Loss of Kindlin-1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction. PLoS Genet. 2008;4(12):e1000289.
61. Moser M, Nieswandt B, Ussar S, Pozgajova M, Fässler R. Kindlin-3 is essential for integrin activation and platelet aggregation. Nat Med. 2008;14(3):325-330.
62. Kuijpers TW, van de Vijver E, Weterman MA, et al. LAD-1/variant syndrome is caused by mutations in FERMT3. Blood. 2009;113(19):4740-4746.
63. Malinin NL, Zhang L, Choi J, et al. A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans. Nat Med. 2009;15(3):313-318.
64. Svensson L, Howarth K, McDowall A, et al. Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation. Nat Med. 2009;15(3):306-312.
65. Ye F, Petrich BG, Anekal P, et al. The mechanism of kindlin-mediated activation of integrin αIIbβ3. Curr Biol. 2013;23(22):2288-2295.
66. Ye F, Snider AK, Ginsberg MH. Talin and kindlin: the one-two punch in integrin activation. Front Med. 2014;8(1):6-16.
67. Cifuni SM, Wagner DD, Bergmeier W. CalDAG-GEFI and protein kinase C represent alternative pathways leading to activation of integrin alphaIIbbeta3 in platelets. Blood. 2008;112(5):1696-1703.
68. Bos JL. Ras-like GTPases. Biochim Biophys Acta. 1997;1333(2):M19-M31.
69. Bivona TG, Wiener HH, Ahearn IM, Silletti J, Chiu VK, Philips MR. Rap1 up-regulation and activation on plasma membrane regulates T cell adhesion. J Cell Biol. 2004;164(3):461-470.
70. Mor A, Wynne JP, Ahearn IM, Dustin ML, Du G, Philips MR. Phospholipase D1 regulates lymphocyte adhesion via upregulation of Rap1 at the plasma membrane. Mol Cell Biol. 2009;29(12):3297-3306.
71. Bos JL, de Rooij J, Reedquist KA. Rap1 signalling: adhering to new models. Nat Rev Mol Cell Biol. 2001;2(5):369-377.
72. Stork PJ, Dillon TJ. Multiple roles of Rap1 in hematopoietic cells: complementary versus antagonistic functions. Blood. 2005;106(9):2952-2961.
73. Scheele JS, Marks RE, Boss GR. Signaling by small GTPases in the immune system. Immunol Rev. 2007;218:92-101.
74. Duchniewicz M, Zemojtel T, Kolanczyk M, Grossmann S, Scheele JS, Zwartkruis FJ. Rap1A-deficient T and B cells show impaired integrin-mediated cell adhesion. Mol Cell Biol. 2006;26(2):643-653.
75. Sebzda E, Bracke M, Tugal T, Hogg N, Cantrell DA. Rap1A positively regulates T cells via integrin activation rather than inhibiting lymphocyte signaling. Nat Immunol. 2002;3(3):251-258.
76. Chu H, Awasthi A, White GC II, Chrzanowska-Wodnicka M, Malarkannan S. Rap1b regulates B cell development, homing, and T cell-dependent humoral immunity. J Immunol. 2008;181(5):3373-3383.
77. Chrzanowska-Wodnicka M, Smyth SS, Schoenwaelder SM, Fischer TH, White GC II. Rap1b is required for normal platelet function and hemostasis in mice. J Clin Invest. 2005;115(3):680-687.
78. Torti M, Ramaschi G, Sinigaglia F, Lapetina EG, Balduini C. Glycoprotein IIb-IIIa and the translocation of Rap2B to the platelet cytoskeleton. Proc Natl Acad Sci USA. 1994;91(10):4239-4243.
79. Katagiri K, Maeda A, Shimonaka M, Kinashi T. RAPL, a Rap1-binding molecule that mediates Rap1-induced adhesion through spatial regulation of LFA-1. Nat Immunol. 2003;4(8):741-748.
80. Lafuente EM, van Puijenbroek AA, Krause M, et al. RIAM, an Ena/VASP and Profilin ligand, interacts with Rap1-GTP and mediates Rap1-induced adhesion. Dev Cell. 2004;7(4):585-595.
81. Liu L, Aerbajinai W, Ahmed SM, Rodgers GP, Angers S, Parent CA. Radil controls neutrophil adhesion and motility through β2-integrin activation. Mol Biol Cell. 2012;23(24):4751-4765.
82. Gotoh T, Hattori S, Nakamura S, et al. Identification of Rap1 as a target for the Crk SH3 domain-binding guanine nucleotide-releasing factor C3G. Mol Cell Biol. 1995;15(12):6746-6753.
83. Gutiérrez-Herrero S, Maia V, Gutiérrez-Berzal J, et al. C3G transgenic mouse models with specific expression in platelets reveal a new role for C3G in platelet clotting through its GEF activity. Biochim Biophys Acta. 2012;1823(8):1366-1377.
84. Ichiba T, Kuraishi Y, Sakai O, et al. Enhancement of guanine-nucleotide exchange activity of C3G for Rap1 by the expression of Crk, CrkL, and Grb2. J Biol Chem. 1997;272(35):22215-22220.
85. Arai A, Nosaka Y, Kohsaka H, Miyasaka N, Miura O. CrkL activates integrin-mediated hematopoietic cell adhesion through the guanine nucleotide exchange factor C3G. Blood. 1999;93(11):3713-3722.
86. Arai A, Nosaka Y, Kanda E, Yamamoto K, Miyasaka N, Miura O. Rap1 is activated by erythropoietin or interleukin-3 and is involved in regulation of beta1 integrin-mediated hematopoietic cell adhesion. J Biol Chem. 2001;276(13):10453-10462.
87. Nolz JC, Nacusi LP, Segovis CM, et al. The WAVE2 complex regulates T cell receptor signaling to integrins via Abl- and CrkL-C3G-mediated activation of Rap1. J Cell Biol. 2008;182(6):1231-1244.
88. Smit L, van der Horst G, Borst J. Sos, Vav, and C3G participate in B cell receptor-induced signaling pathways and differentially associate with Shc-Grb2, Crk, and Crk-L adaptors. J Biol Chem. 1996;271(15):8564-8569.
89. Quilliam LA, Rebhun JF, Castro AF. A growing family of guanine nucleotide exchange factors is responsible for activation of Ras-family GTPases. Prog Nucleic Acid Res Mol Biol. 2002;71:391-444.
90. Katagiri K, Shimonaka M, Kinashi T. Rap1-mediated lymphocyte function-associated antigen-1 activation by the T cell antigen receptor is dependent on phospholipase C-gamma1. J Biol Chem. 2004;279(12):11875-11881.
91. Bergmeier W, Goerge T, Wang HW, et al. Mice lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III. J Clin Invest. 2007;117(6):1699-1707.
92. Crittenden JR, Bergmeier W, Zhang Y, et al. CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation. Nat Med. 2004;10(9):982-986.
93. Canault M, Ghalloussi D, Grosdidier C, et al. Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding. J Exp Med. 2014;211(7):1349-1362.
94. de Rooij J, Zwartkruis FJ, Verheijen MH, et al. Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature. 1998;396(6710):474-477.
95. Kawasaki H, Springett GM, Mochizuki N, et al. A family of cAMP-binding proteins that directly activate Rap1. Science. 1998;282(5397):2275-2279.
96. Murphy MM, Zayed MA, Evans A, et al. Role of Rap1 in promoting sickle red blood cell adhesion to laminin via BCAM/LU. Blood. 2005;105(8):3322-3329.
97. Lorenowicz MJ, van Gils J, de Boer M, Hordijk PL, Fernandez-Borja M. Epac1-Rap1 signaling regulates monocyte adhesion and chemotaxis. J Leukoc Biol. 2006;80(6):1542-1552.
98. Kuiperij HB, de Rooij J, Rehmann H, et al. Characterisation of PDZ-GEFs, a family of guanine nucleotide exchange factors specific for Rap1 and Rap2. Biochim Biophys Acta. 2003;1593(2-3):141-149.
99. Yajnik V, Paulding C, Sordella R, et al. DOCK4, a GTPase activator, is disrupted during tumorigenesis. Cell. 2003;112(5):673-684.
100. Polakis PG, Rubinfeld B, Evans T, McCormick F. Purification of a plasma membrane-associated GTPase-activating protein specific for rap1/Krev-1 from HL60 cells. Proc Natl Acad Sci USA. 1991;88(1):239-243.
101. Mochizuki N, Ohba Y, Kiyokawa E, et al. Activation of the ERK/MAPK pathway by an isoform of rap1GAP associated with G alpha(i). Nature. 1999;400(6747):891-894.
102. Hattori M, Tsukamoto N, Nur-e-Kamal MS, et al. Molecular cloning of a novel mitogen-inducible nuclear protein with a Ran GTPase-activating domain that affects cell cycle progression. Mol Cell Biol. 1995;15(1):552-560.
103. Kurachi H, Wada Y, Tsukamoto N, et al. Human SPA-1 gene product selectively expressed in lymphoid tissues is a specific GTPase-activating protein for Rap1 and Rap2. Segregate expression profiles from a rap1GAP gene product. J Biol Chem. 1997;272(44):28081-28088.
104. Ishida D, Kometani K, Yang H, et al. Myeloproliferative stem cell disorders by deregulated Rap1 activation in SPA-1-deficient mice. Cancer Cell. 2003;4(1):55-65.
105. Schultess J, Danielewski O, Smolenski AP. Rap1GAP2 is a new GTPase-activating protein of Rap1 expressed in human platelets. Blood. 2005;105(8):3185-3192.
106. Wynne JP, Wu J, Su W, et al. Rap1-interacting adapter molecule (RIAM) associates with the plasma membrane via a proximity detector. J Cell Biol. 2012;199(2):317-330.
107. Ménasché G, Kliche S, Chen EJ, Stradal TE, Schraven B, Koretzky G. RIAM links the ADAP/SKAP-55 signaling module to Rap1, facilitating T-cell-receptor-mediated integrin activation. Mol Cell Biol. 2007;27(11):4070-4081.
108. Han J, Lim CJ, Watanabe N, et al. Reconstructing and deconstructing agonist-induced activation of integrin alphaIIbbeta3. Curr Biol. 2006;16(18):1796-1806.
109. Lee HS, Lim CJ, Puzon-McLaughlin W, Shattil SJ, Ginsberg MH. RIAM activates integrins by linking talin to ras GTPase membrane-targeting sequences. J Biol Chem. 2009;284(8):5119-5127.
110. Lee HS, Anekal P, Lim CJ, Liu CC, Ginsberg MH. Two modes of integrin activation form a binary molecular switch in adhesion maturation. Mol Biol Cell. 2013;24(9):1354-1362.
111. Lagarrigue F, Vikas Anekal P, Lee HS, et al. A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration. Nat Commun. 2015;6:8492.
112. Coló GP, Lafuente EM, Teixidó J. The MRL proteins: adapting cell adhesion, migration and growth. Eur J Cell Biol. 2012;91(11-12):861-868.
113. Stritt S, Wolf K, Lorenz V, et al. Rap1-GTP-interacting adaptor molecule (RIAM) is dispensable for platelet integrin activation and function in mice. Blood. 2015;125(2):219-222.
114. Klapproth S, Sperandio M, Pinheiro EM, et al. Loss of the Rap-1 effector RIAM results in leukocyte adhesion deficiency due to impaired beta2 integrin function in mice. Blood. 2015;126(25):2704-2712.
115. Su W, Wynne J, Pinheiro EM, et al. Rap1 and its effector RIAM are required for lymphocyte trafficking. Blood. 2015;126(25):2695-2703.
116. Zeiler M, Moser M, Mann M. Copy number analysis of the murine platelet proteome spanning the complete abundance range. Mol Cell Proteomics. 2014;13(12):3435-3445.
117. Medraño-Fernandez I, Reyes R, Olazabal I, et al. RIAM (Rap1-interacting adaptor molecule) regulates complement-dependent phagocytosis. Cell Mol Life Sci. 2013;70(13):2395-2410.
118. Mitroulis I, Alexaki VI, Kourtzelis I, Ziogas A, Hajishengallis G, Chavakis T. Leukocyte integrins: role in leukocyte recruitment and as therapeutic targets in inflammatory disease. Pharmacol Ther. 2015;147:123-135.
119. Yonekawa K, Harlan JM. Targeting leukocyte integrins in human diseases. J Leukoc Biol. 2005;77(2):129-140.