ArticleProceedings of the National Academy of Sciences of the United States of America2019
Molecular basis for autoinhibition of RIAM regulated by FAK in integrin activation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 28 citations in OpenAlex.
- Regulated RIAM-Talin Engagement Controls Adhesion Stability and Mechanical Output.bioRxiv : the preprint server for biology · 2026Article
- Mechanosensitive biochemical imprinting of the talin interaction with DLC1 regulates RhoA activity and cardiomyocyte remodeling.Science advances · 2025Article
- Factors that determine cell fate in mitotically arrested cancer cells.Frontiers in cell and developmental biology · 2025Article
- Humanized anti-CD11d monoclonal antibodies suitable for basic research and therapeutic applications.Antibody therapeutics · 2025Article
- Inhibition of talin-induced integrin activation by a double-hit stapled peptide.Structure (London, England : 1993) · 2023Article
- ConFERMing the role of talin in integrin activation and mechanosignaling.Journal of cell science · 2023Article
- Integrin Regulators in Neutrophils.Cells · 2022Review
- Truncated O-Glycan-Bearing MUC16 Enhances Pancreatic Cancer Cells Aggressiveness via α4β1 Integrin Complexes and FAK Signaling.International journal of molecular sciences · 2022Article
- Structural, biochemical, and functional properties of the Rap1-Interacting Adaptor Molecule (RIAM).Biomedical journal · 2022Review
- The Connection Between Rap1 and Talin1 in the Activation of Integrins in Blood Cells.Frontiers in cell and developmental biology · 2022Review
- Phosphorylation of RIAM by src promotes integrin activation by unmasking the PH domain of RIAM.Structure (London, England : 1993) · 2021Article
- Manipulation of Focal Adhesion Signaling by Pathogenic Microbes.International journal of molecular sciences · 2021Review
- Phosphorylation of RIAM Activates Its Adaptor Function in Mediating Integrin Signaling.Journal of cellular signaling · 2021Article
- The Multiple Roles of the Cytosolic Adapter Proteins ADAP, SKAP1 and SKAP2 for TCR/CD3 -Mediated Signaling Events.Frontiers in immunology · 2021Review
- Talin dissociates from RIAM and associates to vinculin sequentially in response to the actomyosin force.Nature communications · 2020Article
- The Mystery of Rap1 Suppression of Oncogenic Ras.Trends in cancer · 2020Review
- Molecular Response in Intestinal and Immune Tissues toFrontiers in veterinary science · 2020Article
- Inside-out signaling through FAK-integrin axis may regulate circulating cancer cell metastatic adhesion.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Adhesions Assemble!-Autoinhibition as a Major Regulatory Mechanism of Integrin-Mediated Adhesion.Frontiers in molecular biosciences · 2019Review
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7 authors at 3 institutions in 1 country.
Funding
Abstract
RAP1-interacting adapter molecule (RIAM) mediates RAP1-induced integrin activation. The RAS-association (RA) segment of the RA-PH module of RIAM interacts with GTP-bound RAP1 and phosphoinositol 4,5 bisphosphate but this interaction is inhibited by the N-terminal segment of RIAM. Here we report the structural basis for the autoinhibition of RIAM by an intramolecular interaction between the IN region (aa 27-93) and the RA-PH module. We solved the crystal structure of IN-RA-PH to a resolution of 2.4-Å. The structure reveals that the IN segment associates with the RA segment and thereby suppresses RIAM:RAP1 association. This autoinhibitory configuration of RIAM can be released by phosphorylation at Tyr45 in the IN segment. Specific inhibitors of focal adhesion kinase (FAK) blocked phosphorylation of Tyr45, inhibited stimulated translocation of RIAM to the plasma membrane, and inhibited integrin-mediated cell adhesion in a Tyr45-dependent fashion. Our results reveal an unusual regulatory mechanism in small GTPase signaling by which the effector molecule is autoinhibited for GTPase interaction, and a modality of integrin activation at the level of RIAM through a FAK-mediated feedforward mechanism that involves reversal of autoinhibition by a tyrosine kinase associated with integrin signaling.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.