ITGB1 (integrin beta-1, CD29, human, P05556) review notes

Automated deep research was unavailable for this review (no provider keys), so no
-deep-research-*.md file exists. These notes are based on the UniProt record, the 349 GOA
rows and the cached publications in publications/. Many primary papers behind the GOA rows
are abstract-only in the cache (full_text_available: false); decisions on those rows are
limited to what the abstract says, and experimental rows were not removed on that basis.

Core biology

• Integrins are heterodimeric ECM receptors, old in evolution: "Integrins are cell adhesion
  receptors that are evolutionary old and that play important roles during developmental and
  pathological processes." PMID:19693543
• Beta-1 pairs with 12 alpha subunits (alpha1-11, alphaV) (UniProt SUBUNIT). These
  heterodimers are the main receptors for collagens (alpha1, 2, 10, 11), laminins (alpha3, 6,
  7), fibronectin (alpha5, alpha4, alpha8, alphaV) and the cell-surface counter-receptor
  VCAM1 (alpha4, alpha9) (UniProt FUNCTION).
• alpha5beta1 is the prototypic fibronectin receptor: "Integrin α5β1 is a major cellular
  receptor for the extracellular matrix protein fibronectin and plays a fundamental role
  during mammalian development." PMID:22451694
• Bidirectional link: "Integrin α5β1 connects to the FN ligand, a major component of the ECM,
  through its extracellular domains and to the actin cytoskeleton through its cytoplasmic tail
  domains in combination with accessory factors" PMID:33962943
• Divalent cations: "The integrin βI domain contains three functional metal ion pockets
  exhibiting clear densities, namely, MIDAS, ADMIDAS" PMID:33962943; the FN-alpha5beta1
  cryo-EM shows "key interactions centered at R1445 and Y1446 of FN and D137 of ADMIDAS in β1
  βI domain provide an additional anchoring point that triggers the opening of α5β1"
  PMID:33962943. The resting buffer is Ca2+/Mg2+, Mn2+ activates.
• Adhesion receptor activity is regulated from inside: "activation of endogenous EphA2 kinase
  induces an inactive conformation of integrins and inhibits cell spreading, migration and
  integrin-mediated adhesion" PMID:10655584.
• Cytoplasmic tail partners (all with direct-binding evidence in the cited papers):
• talin: "the interaction between integrin and talin was greatly enhanced by
  PI4,5P(2)-induced talin activation" PMID:11279249; NMR of beta1A/beta1D tails with
  talin1/2 PMID:21134644; ICAP-1 competes with talin PMID:12473654.
• filamin: "the cytoplasmic domain of beta1-integrin specifically interacts with the
  cytoskeletal protein filamin" PMID:9722563; FLNa pull-downs PMID:17690686.
• ICAP-1 (ITGB1BP1), specific to beta1 and requiring the NPXY motif PMID:9281591.
• Rab25 (direct, tail) PMID:17925226; Abl2/Arg kinase domain binds the membrane-proximal
  tail PMID:25694433; FAK "is directly recruited by integrin β1" PMID:26763945.
• Extracellular partners beyond ECM: fractalkine chemokine domain (alpha4beta1 coreceptor)
  [PMID:23125415, PMID:24789099]; CD40L (alpha5beta1) PMID:31331973; ADAM17 and ADAM9
  disintegrin domains [PMID:14970227, PMID:30455686, PMID:17704059]; seprase/FAP docking at
  invadopodia (alpha3beta1) PMID:10455171; viral and fungal ligands (EBV BMRF-2
  PMID:12592401, Rhizopus CotH7 PMID:32487760).

GO-CAM

gocams/index.tsv has ITGB1 in two human models:
- 666b894f00000196 "CD93/Multimerin-2/beta1 integrin complex function in angiogenesis":
coreceptor activity (GO:0015026), angiogenesis, plasma membrane.
- 689e7a5d00003515 "Ephrin-A1/EPHA2 negative regulation of cell adhesion mediated by
integrin": cell adhesion receptor activity (GO:0004895), integrin-mediated signaling
pathway, focal adhesion. This matches the core MF chosen here.

Decisions by group (349 rows)

• Protein binding (74 rows). Repository policy: MODIFY where the cited paper supports a
  more informative MF and the partner defines one; otherwise REMOVE as uninformative (removal
  does not mean the interaction is false).
• talin partners -> GO:1990147 talin binding (11279249, 12473654, 21134644, 21947080).
• filamin partners -> GO:0031005 filamin binding (9722563, 17690686, 18177638, 16076904).
• FN1 -> fibronectin binding (33962943); fibrillin-1 -> GO:0050840 extracellular matrix binding (12807887, 17158881; GO has no fibrillin-binding term).
• fractalkine -> GO:0019960 C-X3-C chemokine binding (24789099).
• Rab25 -> GO:0031267 small GTPase binding (17925226). Rab21 (16754960) was REMOVED: the
  paper places Rab21 on alpha-chain tails, not beta1.
• Abl2 -> GO:1990782 protein tyrosine kinase binding (25694433).
• ADAM17/ADAM9 disintegrin ligands -> GO:0002020 protease binding (14970227, 22413019,
  30455686, 17704059), matching the existing protease-binding row for seprase.
• midkine (MDK) rows from 15466886 -> GO:0038023 signaling receptor activity ("alpha4beta1-
  and alpha6beta1-integrins are functional receptors for midkine").
• EBV BMRF-2 -> GO:0001618 virus receptor activity (12592401).
• integrin TM domain heterodimers (14681217) -> GO:0046982 protein heterodimerization activity.
• Integrin alpha-subunit partners (ITGA2/4/5/6) REMOVED: subunit pairing is captured by the
  integrin alphaX-beta1 complex CC rows.
• High-throughput Y2H / interactome rows (32814053, 33961781, 35384245, 30021884) REMOVED.
• PMID:10676904 is a wrong identifier: PubMed (esummary checked) and the cache both give a
  bovine oocyte culture paper, which cannot support an ITGB1-FLNB interaction. REMOVED
  under the protein-binding policy anyway; flagged WRONG_IDENTIFIER in references.
• Removed process rows. homophilic cell-cell adhesion (TAS 10201960): integrins bind
  heterophilic ligands, and the cited paper only reports eotaxin up-regulating CD29.
  cellular defense response (TAS 10201960): same paper, expression change only.
• Over-annotated. B cell differentiation (IC from 1715889: the abstract only suggests
  adhesion "may be required for normal early B cell development"); cell development,
  regulation of developmental process (ARBA, too general); response to muscle activity,
  cellular response to low-density lipoprotein particle stimulus (mouse-derived
  expression/response terms); melanosome (proteomics); cytoplasm (IDA, platelet paper;
  ITGB1 is a type I membrane protein); cadherin binding HDA (E-cadherin proximity
  proteomics); mesodermal cell differentiation (IEP and ARBA; the cited paper is on
  endoderm differentiation via ITGA5/ITGAV); ARBA protein-containing complex binding;
  signaling receptor complex (23382219, SNX17 cargo screen).
• MODIFY of non-binding rows. calcium-independent cell-matrix adhesion (IGI 19651211)
  -> cell adhesion mediated by integrin: the abstract shows RGD-dependent beta1 adhesion but
  says nothing about calcium, and beta1 ligand binding uses Ca2+ sites (ADMIDAS/SyMBS).
  protein-containing complex binding IPI (25336636, CDH17 RGD ligand) -> cadherin binding.
• UNDECIDED. actin binding IDA (16803572, platelet dystrophin/utrophin co-IP; abstract
  does not show direct actin binding by beta1); maintenance of blood-brain barrier NAS
  (30280653: the cached abstract of the review does not mention integrins).
• NOT rows (24036928): beta1 knockdown did not reduce TGF-beta-induced ventral stress
  fibres ("Knockdown of integrin-β1 by siRNA did not reduce TGF-β1-induced VSFs"). Both NOT
  annotations accepted.

Premetazoan context (ancestral vs animal-specific)

• Integrin beta and alpha are older than animals. Sebé-Pedrós et al. found "four integrin β
  and four integrin α genes in C. owczarzaki", and one of each in the apusozoan
  Amastigomonas PMID:20479219.
• The ancestral beta subunits already have the key motifs: the cation-binding sites "are well
  conserved in the different nonmetazoan integrin β, except for C. owczarzaki integrin β4",
  and the cytoplasmic alpha-interacting motif and NPXY motif "are well conserved in C.
  owczarzaki integrin β1–β3 and Amastigomonas sp. integrin β" PMID:20479219.
• Choanoflagellates lost them: "Integrin α and β and several other components of the integrin
  adhesion complex are absent from choanoflagellates and fungi and were presumably lost
  independently in these lineages" PMID:20479219. The putative M. brevicollis integrin
  alpha (XP_001749484) failed their criteria and clusters with bacterial FG-GAP proteins.
• Capsaspora integrin beta2 is used for substrate adhesion: Capsaspora "adheres to surfaces
  using actin-dependent filopodia", "integrin β2 and its associated protein vinculin localize
  as distinct patches in the filopodia", and an anti-integrin beta2 antibody inhibited
  adhesion to fibronectin-coated surfaces [PMID:32857975, abstract only].
• Caveat: Capsaspora integrin betas are a lineage-specific expansion ("lineage-specific
  diversifications ... of both integrin α and β have occurred within the C. owczarzaki
  lineage" PMID:20479219); they are not orthologs of ITGB1 specifically. The ancestral
  claim is for the integrin beta subunit family, not for ITGB1 as a paralog.
• Talin/vinculin are older still (amoebozoans) and were co-opted to integrins
  PMID:20479219; see the TLN1 and VCL reviews.

So, on current evidence:
- Ancestral (holozoan or older): alpha/beta heterodimeric receptor; divalent-cation
(MIDAS/ADMIDAS) dependent ligand binding; cytoplasmic NPXY motif for adaptor (talin) binding;
cell-substrate adhesion through actin-rich protrusions with vinculin. Capsaspora adhesion is
enhanced by mammalian fibronectin in assays PMID:32857975, but the native Capsaspora
ligand is not identified in the papers read here.
- Animal-specific (on current evidence; not separately sourced here): binding to the
specific animal ECM ligands annotated on ITGB1 (fibronectin, collagens, laminins), cell-cell
adhesion via counter-receptors (VCAM1, ADAMs), coreceptor roles in chemokine/growth factor
signalling, angiogenesis, leukocyte trafficking, myogenesis, osteoclast and neural
functions. These are tissue-level roles of the beta1 paralog in a multicellular body.