ReviewCell Biology

The adaptor molecule RIAM integrates signaling events critical for integrin-mediated control of immune function and cancer progression

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Sci. Signal.  22 Aug 2017:
Vol. 10, Issue 493, eaam8298
DOI: 10.1126/scisignal.aam8298

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Gloss

Rap1-interacting molecule (RIAM) is a multidomain protein that regulates multiple functions in immune cells. RIAM contains an RA (RalGDS/AF-6 or Ras-association) domain, a PH (pleckstrin homology) domain, and two proline-rich regions. It also contains two putative coiled-coil regions at the amino (N) terminus. The simultaneous interaction of PH and RA domains with their partners results in relocation of RIAM to the plasma membrane upon cell activation. Through its N terminus, RIAM interacts with various sites of talin, leading to talin-mediated activation of integrins. RIAM controls cell adhesion and migration and is involved in the regulation of innate and adaptive immune responses and in the invasion and migration of cancer cells. Thus, RIAM might be an attractive therapeutic target to modulate immune cell processes mediated by β2 integrin interactions in immune cells but also to block cancer cell migration. This review includes four figures and 95 references.

Abstract

Lymphocyte activation requires adhesion to antigen-presenting cells. This is a critical event linking innate and adaptive immunity. Lymphocyte adhesion is accomplished through LFA-1, which must be activated by a process referred to as inside-out integrin signaling. Among the few signaling molecules that have been implicated in inside-out integrin activation in hematopoietic cells are the small guanosine triphosphatase (GTPase) Rap1 and its downstream effector Rap1-interacting molecule (RIAM), a multidomain protein that defined the Mig10-RIAM-lamellipodin (MRL) class of adaptor molecules. Through its various domains, RIAM is a critical node of signal integration for activation of T cells, recruits monomeric and polymerized actin to drive actin remodeling and cytoskeletal reorganization, and promotes inside-out integrin signaling in T cells. As a regulator of inside-out integrin activation, RIAM affects multiple functions of innate and adaptive immunity. The effects of RIAM on cytoskeletal reorganization and integrin activation have implications in cell migration and trafficking of cancer cells. We provide an overview of the structure and interactions of RIAM, and we discuss the implications of RIAM functions in innate and adaptive immunity and cancer.

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