Abstract 3927: Structural and mechanistic insights into the roles of RIAM in integrin signaling

Abstract

Abstract Changes in integrin signaling promotes tumor cell proliferation, metastasis and survival. The Rap1-interacting adaptor molecule (RIAM) mediates integrin activation by responding to Rap1 activation and recruiting talin, the integrin activator, to the plasma membrane (PM). The structural details of how RIAM is recognized by Rap1 and in turn recruits talin are lacking. We have elucidated the specificities for RIAM interacting with Rap1 and talin via X-ray crystallography and functional analyses. Crystal structure of Rap1 in complex with the central structural module of RIAM reveals essential specificity determinants, especially a Lys31 residue that is oppositely charged in other Ras GTPases. Furthermore, our study on the RIAM:talin interaction suggests that the talin-binding site 1 (TBS1) of RIAM is required for recruiting cytoplasmic talin to the PM, primarily via an interaction with the R8 domain of talin. Interestingly, an unexpected kink in the helical TBS1 fragment is required for inducing integrin activation. These characteristics are not seen in other related molecules including the highly homologous Lpd, providing the molecular basis for the specific signaling function of RIAM that mediates the integrin activation. Citation Format: Jinhua Wu. Structural and mechanistic insights into the roles of RIAM in integrin signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3927. doi:10.1158/1538-7445.AM2015-3927