{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:04:09Z","timestamp":1790053449550,"version":"4.0.1"},"reference-count":122,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["25K09637"],"award-info":[{"award-number":["25K09637"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["25K02274"],"award-info":[{"award-number":["25K02274"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Takeda Science Foundation","id":[{"id":"https:\/\/ror.org\/02y123g31","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/02y123g31","id-type":"ROR","asserted-by":"publisher"}]},{"name":"TERUMO LIFE SCIENCE FOUNDATION"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Integrins play a central role in a wide range of biological processes, including development, tissue homeostasis, immune responses, and disease progression. Their activation is traditionally explained by two major signaling modes: inside-out signaling, which converts integrins to ligand-competent and high-affinity states through intracellular activators, including the Rap1-talin-kindlin axis, and outside-in signaling, which transduces ligand engagement into cytoskeletal coupling and downstream signaling. Recent findings indicate that this division is incomplete. Ligand-engaged integrins can also generate spatially organized signaling platforms that feed back to enhance integrin adhesiveness per se. In this revised view, outside-in signaling does not merely report the completion of adhesion but can amplify both affinity, by stabilizing activator binding and high-affinity conformations, and avidity, by promoting integrin clustering and local integrin accumulation. This feedback mechanism is most extensively characterized in lymphocytes, where LFA1 (\u03b1L\u03b22) outside-in signaling activates Rap1 and recruits talin1 and kindlin-3, increases LFA1-ICAM1 binding stability, and promotes LFA1 transport through ATG8\/LC3-associated machinery. Importantly, this ATG8\/LC3-dependent process, named LAPTIN, does not represent canonical degradative autophagy but rather defines an integrin-induced LC3-associated protein transport pathway that promotes LFA1 accumulation. These observations position outside-in signaling as a potential \u201cdetonator\u201d of positive-feedback activation rather than a passive consequence of ligand binding. In this review, we summarize the structural and cellular basis of affinity and avidity regulation, compare activation-promoting outside-in and related feedback mechanisms across adherent-cell, leukocyte, and platelet systems, and discuss how outside-in\u2013based trafficking, LC3-associated protein transport, metabolic signaling, and mechanical force reveal shared regulatory principles alongside integrin-specific implementations, with potential implications for therapeutic targeting.<\/jats:p>","DOI":"10.3390\/biom16091358","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:01:38Z","timestamp":1789981298000},"page":"1358","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Outside-In Signaling as a Detonator-like Stimulus of Integrin Activation by Promoting Both Affinity and Avidity"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6624-5989","authenticated-orcid":false,"given":"Naoyuki","family":"Kondo","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Hirakata 573-1010, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuo","family":"Kinashi","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Hirakata 573-1010, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1242\/dev.119.4.1093","article-title":"Embryonic mesodermal defects in alpha 5 integrin-deficient mice","volume":"119","author":"Yang","year":"1993","journal-title":"Development"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1083\/jcb.200106124","article-title":"Mystery solved: Discovery of a novel integrin ligand in the developing kidney","volume":"154","author":"Miner","year":"2001","journal-title":"J. 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