ITGB5

ITGB5 (integrin β5) pairs with αv to form the αvβ5 heterodimer, which functions as an adhesion and phagocytic receptor in normal tissue and as a context-dependent driver of receptor trafficking and pro-survival signaling in cancer (PMID:22566632, PMID:37149115). In the retinal pigment epithelium, αvβ5 activity is required for the diurnal phagocytic rhythm: loss of ITGB5 abolishes the circadian peak of phosphatidylserine exposure at rod outer segment tips that precedes shedding and phagocytosis (PMID:22566632). On intestinal epithelium, ITGB5 acts as a direct receptor for ETEC F4ac fimbriae, binding the FaeG adhesin and mediating bacterial adhesion (PMID:31921118). In cancer, ITGB5 operates as a signaling scaffold: it interacts with EPS15 to block EGFR lysosomal degradation and activate AKT-mTOR and MAPK signaling, with a CSNK1A1-dependent phosphorylation feedback loop reinforcing the ITGB5–EPS15 interaction (PMID:37149115), and it binds TGFBR2 and SNX17 to promote endosomal recycling of TGFBR2, sustaining TGFβ-driven EMT (PMID:38729557). Downstream, ITGB5 engages FAK/Src and PI3K/AKT/ERK signaling to promote invasion and proliferation (PMID:40119353, PMID:41857463). ITGB5 abundance is itself controlled at multiple levels: USP1-mediated deubiquitination stabilizes the protein (PMID:41857463), NAT10-mediated ac4C modification stabilizes its mRNA (PMID:40119353), and STAU1 binding to its 3' UTR stabilizes the transcript within a STAU1–ITGB5–FOXP3 feedback loop (PMID:41796846).

1. 2012 High

   Established that RPE αvβ5 integrin activity, not intrinsic photoreceptor signaling, drives the circadian phosphatidylserine demarcation of rod outer segment tips required for diurnal phagocytosis.

   Evidence Itgb5-/- mouse retina live imaging with annexin V/pSIVA biosensors, compared to Mfge8-/- and wild-type, plus RPE phagocytosis assays with PS blockade

   PMID:22566632

   Open questions at the time

   • Does not resolve how ITGB5 senses or transduces the circadian timing cue
   • Downstream cytoplasmic signaling effectors in RPE not defined
2. 2013 Low

   First implicated ITGB5 in intestinal defense against ETEC F4ac, linking it to bacterial adhesion and modulation of mucosal inflammation.

   Evidence siRNA knockdown of ITGB5 in porcine IPEC-J2 cells with bacterial adhesion assay and qPCR of inflammatory genes

   PMID:23922972

   Open questions at the time

   • Single-method knockdown with no direct binding assay
   • Knockdown increased adhesion, complicating the receptor interpretation later refined by direct binding work
   • Mechanism of inflammation modulation undefined
3. 2019 High

   Demonstrated that ITGB5 is a direct physical receptor for the ETEC F4ac fimbrial adhesin FaeG, resolving the adhesion mechanism at the molecular level.

   Evidence GST pull-down of purified FaeG with ITGB5, CRISPR/Cas9 knockout and overexpression in IPEC-J2 cells with bacterial adhesion readouts

   PMID:31921118

   Open questions at the time

   • Binding interface residues not mapped
   • Whether αvβ5 heterodimer or ITGB5 alone mediates binding unaddressed
   • Reconciliation with earlier knockdown adhesion result not provided
4. 2022 Low

   Connected ITGB5 to therapy resistance by showing it facilitates DNA damage repair and MEK/ERK activation to confer radiation resistance in pancreatic cancer.

   Evidence ITGB5 knockdown in PAAD cells with irradiation, DNA damage repair, and MEK/ERK pathway assays

   PMID:36249018

   Open questions at the time

   • Single-lab knockdown with limited mechanistic depth
   • No direct link between ITGB5 and DNA repair machinery established
   • How a surface integrin influences nuclear DNA repair unexplained
5. 2023 Medium

   Defined ITGB5 as a scaffold that protects EGFR from degradation via EPS15, establishing a CSNK1A1-reinforced feedback loop driving AKT-mTOR/MAPK signaling and sorafenib resistance.

   Evidence Co-IP/MS identifying EPS15 and CSNK1A1, reciprocal Co-IP, knockdown/overexpression, EGFR degradation and signaling assays in HCC cells

   PMID:37149115

   Open questions at the time

   • Not independently replicated
   • Direct EPS15-ITGB5 binding interface unmapped
   • CSNK1A1 phosphorylation site on ITGB5 not defined
6. 2024 Medium

   Showed ITGB5 functions as a scaffold linking TGFBR2 to SNX17-mediated endosomal recycling, sustaining TGFβ-driven EMT and metastasis within a TGFβ–ITGB5 feedback loop.

   Evidence Reciprocal Co-IP of ITGB5 with TGFBR2 and SNX17, endosomal recycling and TGFBR2 surface assays, in vitro and in vivo knockdown in gastric cancer

   PMID:38729557

   Open questions at the time

   • Single lab, not independently replicated
   • Direct vs indirect nature of the ternary scaffold not dissected
   • Stoichiometry and binding domains undefined
7. 2024 Low

   Extended ITGB5's pro-tumor signaling roles via FAK/Src, PI3K/AKT, and Src in multiple cancers, with upstream regulation by ENAH and ROS.

   Evidence Knockdown/overexpression with migration, invasion, and signaling assays in OSCC, TSCC, and PDAC microenvironment co-cultures; recombinant ITGB5/ITGB1 protein addition

   PMID:39180583 PMID:39511483 PMID:39719238

   Open questions at the time

   • No direct binding assay between ENAH and ITGB5
   • Pathway phenotypes from single labs without reconstitution
   • Whether effects depend on αvβ5 heterodimer formation untested
8. 2025 Medium

   Identified post-transcriptional control of ITGB5 via NAT10-mediated ac4C modification of its mRNA CDS, stabilizing the transcript to drive ITGB5–pFAK–pSrc signaling and perineural invasion.

   Evidence acRIP-seq/ac4C-seq mapping, NAT10 CRISPR manipulation, mRNA stability assays, DRG co-culture and sciatic nerve in vivo PDAC models

   PMID:40119353

   Open questions at the time

   • Single lab
   • Functional contribution of individual ac4C sites not isolated
   • Generality of NAT10-ITGB5 axis beyond PDAC unknown
9. 2026 Medium

   Revealed two additional layers of ITGB5 stabilization—USP1 deubiquitination of the protein and STAU1 binding to the 3' UTR of its mRNA—each embedded in feedback loops driving disease progression.

   Evidence IP-MS identifying USP1-ITGB5 with deubiquitination and rescue assays in a pancreatitis model; RIP confirming STAU1 3' UTR binding with mRNA stability, FOXP3 phosphorylation, and ChIP in colorectal cancer

   PMID:41796846 PMID:41857463

   Open questions at the time

   • Both single-lab studies
   • USP1 ubiquitination site on ITGB5 not mapped
   • Mechanism by which ITGB5 promotes FOXP3 S418 phosphorylation undefined

• How the diverse cancer scaffolding and trafficking functions of ITGB5 relate to its canonical αvβ5 adhesion-receptor role, and whether they require heterodimerization with αv, remains unresolved.
• No structural model of ITGB5 in its scaffold complexes
• Dependence of intracellular signaling roles on αv pairing untested
• Integration of multiple feedback loops into one regulatory network not established