FGF2 (human, P09038) curation notes

Identity and isoforms

• Basic fibroblast growth factor; heparin-binding growth factor family, beta-trefoil fold.
  [file:human/FGF2/FGF2-uniprot.txt "SIMILARITY: Belongs to the heparin-binding growth factors family."]
• Alternative translation initiation (CUG codons) gives a low-molecular-weight (18 kDa, AUG) form and
  N-terminally extended high-molecular-weight (HMW) forms. UniProt lists four isoforms (P09038-1..-4).
  [file:human/FGF2/FGF2-uniprot.txt "Event=Alternative initiation; Named isoforms=4;"]
• HMW forms are nuclear and form nuclear complexes; FIF/API5 binds HMW FGF2 specifically.
  PMID:11075807

Secretion (unconventional)

• No signal peptide; exported by direct translocation across the plasma membrane, dependent on
  PI(4,5)P2 and HSPGs; Tec kinase phosphorylates FGF2 (Y82 of 18 kDa form = Y215 in UniProt numbering).
  PMID:20230531
• Caspase-1 activity is required for FGF2 secretion in keratinocytes; FGF2 physically associates with
  caspase-1 but is not a substrate. PMID:18329368
• Consequence for GO: the 18 kDa form is genuinely cytosolic before export, so the IBA "cytoplasm"
  annotation is defensible for FGF2 (unlike signal-peptide FGFs such as FGF8).

Receptor binding (core MF)

• Ligand for FGFR1-4, with mitogenic assays across receptor splice variants.
  [file:human/FGF2/FGF2-uniprot.txt "FUNCTION: Acts as a ligand for FGFR1, FGFR2, FGFR3 and FGFR4"]
  PMID:8663044
• Structures: FGF2-FGFR1 2:2 dimer PMID:10490103;
  FGF2-FGFR2 PMID:10830168; 2:2:2 FGF2-FGFR1-heparin PMID:11030354;
  Apert FGFR2 and Pfeiffer/Muenke FGFR1/FGFR3 mutants crystallized with FGF2 [PMID:11390973, PMID:14613973].
• Mouse FGFR1 expressed in CHO cells binds bFGF and signals DNA synthesis and proliferation PMID:2161540.
• Heparin/HS binding: basic canyon on FGF2 PMID:10490103.
  No heparin binding row is currently in GOA for human FGF2, so I proposed it as NEW (MF only; the
  comparator FGF1 is a classical heparin-binding FGF, and heparin-binding is the family's name).
• Integrin alphaVbeta3 binding (Takada lab), proposed as needed for FGF2 signaling
  PMID:28302677. Accepted as integrin binding but not made core: single-lab model.

Extracellular binding partners (from IPI "protein binding" rows)

• FGFR1/FGFR2 (structural and SPR papers; HuRI and RTK interactome screens): converted to FGFR binding.
• FGFBP1 PMID:16257968, PTX3 [PMID:20363749, PMID:22267482], CXCL13 PMID:11708770, caspase-1
  PMID:18329368: these are regulators/sequestrators of FGF2; from the FGF2 side there is no
  informative MF term, so the generic protein binding rows are removed (the interactions are real).
• Intracellular: RPS19 PMID:11716516, CEP57/Translokin PMID:12717444,
  API5/FIF PMID:11075807 -- trafficking/nuclear-function partners; generic binding rows removed.

Nuclear localization

• Exogenous FGF2 is imported into the nucleus after endocytosis and translocation to cytosol, via
  CEP57 and importins PMID:22321063.
• Nuclear association required for mitogenic activity of internalized FGF2 PMID:12717444.

Physiology (in vivo)

• Fgf2-/- mice are viable and fertile; cortical neuron density reduced and wound healing delayed.
  PMID:9576942
• This is the key reason I treated broad embryogenesis terms from rat IEA as over-annotation, and
  the numerous angiogenesis/endothelial terms as non-core outcomes of FGFR signaling (FGF2 is not
  required for developmental angiogenesis in the knockout).

Downstream signaling in endothelial cells

• PI3K and PLCgamma1 activation, Ca2+ rise, Akt S473, migration and tubulogenesis in HUVEC
  PMID:20011604
• Sustained MAPK activation PMID:16756958.

Problem annotations

• GO:0090722 receptor-receptor interaction (IDA, PMID:24157794): FGF2 was the agonist that increased
  FGFR1 homodimerization in FGFR1-5-HT1A heteroreceptor complexes; the MF belongs to the receptors.
  MODIFY -> FGFR binding.
• GO:0030214 hyaluronan catabolic process (IDA, PMID:19577615): abstract says bFGF inhibited HA
  degradation by lowering HYAL2 expression, i.e. an indirect negative effect on expression; the
  ligand does not take part in HA catabolism. Marked as over-annotation.
• GO:0061045 negative regulation of wound healing (IDA, PMID:19577615): based on an in vitro scratch
  ("wound healing") assay of fibrosarcoma cell migration; not tissue wound healing, and in vivo
  FGF2 promotes wound healing PMID:9576942. MODIFY -> negative regulation of fibroblast migration.
• GO:0043537 negative regulation of blood vessel endothelial cell migration (IDA, PMID:18555217):
  abstract describes TSP-1 inhibiting FGF-2-stimulated migration; full text not available, so
  UNDECIDED rather than REMOVE.
• GO:0062072 histone H3K9me2/3 reader activity and derived GO:0006325 chromatin organization
  (IEA from rat Fgf2 via Ensembl Compara): source experiment not visible; UNDECIDED.