Loss of the Rap1 effector RIAM results in leukocyte adhesion deficiency due to impaired β2 integrin function in mice.
Talin is an integrin adaptor, which controls integrin activity in all hematopoietic cells. How intracellular signals promote talin binding to the integrin tail leading to integrin activation is still poorly understood, especially in leukocytes. In vitro studies identified an integrin activation complex whose formation is initiated by the interaction of active, guanosine triphosphate (GTP)-bound Ras-related protein 1 (Rap1) with the adapter protein Rap1-GTP-interacting adapter molecule (RIAM) followed by the recruitment of talin to the plasma membrane. Unexpectedly, loss-of-function studies in mice have shown that the talin-activating role of RIAM is neither required for development nor for integrin activation in platelets. In this study, we show that leukocyte integrin activation critically depends on RIAM both in vitro and in vivo. RIAM deficiency results in a loss of β2 integrin activation in multiple leukocyte populations, impaired leukocyte adhesion to inflamed vessels, and accumulation in the circulation. Surprisingly, however, the major leukocyte β1 integrin family member, α4β1, was only partially affected by RIAM deficiency in leukocytes. Thus, although talin is an essential, shared regulator of all integrin classes expressed by leukocytes, we report that β2 and α4 integrins use different RIAM-dependent and -independent pathways to undergo activation by talin.
Max Planck Institute of Biochemistry, Max Planck Society for the Advancement of Science, Martinsried, Germany; Walter Brendel Center for Experimental Medicine, Ludwig-Maximilians Universität, München, Germany;
Sarah
S
Klapproth
Walter Brendel Center for Experimental Medicine, Ludwig-Maximilians Universität, München, Germany;
Markus
M
Sperandio
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA;
Elaine M
EM
Pinheiro
Walter Brendel Center for Experimental Medicine, Ludwig-Maximilians Universität, München, Germany;
Monika
M
Prünster
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, München, Germany; German Centre for Cardiovascular Research (DZHK), Munich Heart Alliance, Munich, Germany; and Department of Pathology, Amsterdam Medical Center, Amsterdam, The Netherlands.
Oliver
O
Soehnlein
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA;
Frank B
FB
Gertler
Max Planck Institute of Biochemistry, Max Planck Society for the Advancement of Science, Martinsried, Germany;
Reinhard
R
Fässler
Max Planck Institute of Biochemistry, Max Planck Society for the Advancement of Science, Martinsried, Germany;
Markus
M
Moser
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D018821:CD18 Antigens / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002469:Cell Separation; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D005434:Flow Cytometry; D039041:Integrin alpha4beta1 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016608:Talin / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D018821:CD18 Antigens; D039041:Integrin alpha4beta1; D008565:Membrane Proteins; C521189:RIAM protein, mouse; D016608:Talin; D020827:rap1 GTP-Binding Proteins