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Dr. Frédéric Lagarrigue - Integrin inside-out signaling in blood cells: multiple and cell-type specific pathways

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Frédéric Lagarrigue

IPBS, Toulouse

Integrin inside-out signaling in blood cells: multiple and cell-type specific pathways

Blood cells can dynamically regulate the affinity of integrin adhesion receptors, in a process operationally defined as integrin activation, to serve a wide range of immune functions and hemostasis. The adapter talin binds to the integrin β cytoplasmic domain to induce changes in integrin conformation and affinity for their ligands. The effects of deletion of talin in murine leukocytes and platelets have unequivocally confirmed its importance in integrin activation. Rap1 GTPases bind effectors, such as RIAM, to enable talin to induce integrin activation. We previously showed that RIAM is a critical player in lymphocyte adhesion and activation. Here, I will first review our recent findings that identify a novel alternative pathway involving a direct Rap1-talin interaction to promote integrin activation. Preliminary analysis of mice harboring mutations in talin that prevent binding to Rap1 demonstrate the importance of such interactions for platelet functions in vivo. Together with my postdoctoral research, these findings lead to the paradigm that signaling events in leukocytes operate in both a cell−type and integrin−specific manner, thereby providing unique avenues to manipulate recruitment of particular leukocytes into specific tissues. I recently joined the group of Isabelle Maridonneau-Parini at IPBS and, in the second part of my talk, I will introduce my new endeavor to decipher the adhesion signaling that operate in macrophage migration and tissue infiltration. We intend to devise an innovative approach to block specifically the recruitment of macrophages into tumors. We will use unique knockin and knockout mouse models to establish the key regulators of integrin signaling that control adhesion and migration of macrophages.

Selected references

•    Gingras*, Lagarrigue* et al. (2019) Rap1 binding and a lipid-dependent helix in talin F1 domain promote integrin activation in tandem. J Cell Biol doi: 10.1083/jcb.201810061
•    Lagarrigue et al. (2018) Rap1 binding to the talin 1 F0 domain makes a minimal contribution to murine platelet GPIIb-IIIa activation. Blood Adv 2(18):2358-2368
•    Lagarrigue et al. (2017) Cutting Edge: Loss of T cell RIAM precludes conjugate formation with APC and prevents immune-mediated diabetes. J Immunol 198(9):3410-15
•    Lagarrigue et al. (2016) The Rap1-RIAM-talin axis of integrin activation and blood cell function. Blood 128(4):479-87
•    Ye*, Lagarrigue* and Ginsberg (2014) SnapShot: talin and the modular nature of the integrin adhesome. Cell 156(6):1340-40 e1341

 

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21 May

11:00 - 12:00

Seminar room - IPBS - Campus 205