btl (breathless) – manual literature synthesis

No deep-research API was available for this review. This file was written by hand from
the cached publications in publications/ and the UniProt record (Q09147, FGFR2_DROME).
Each statement carries its source.

Identity and structure

• Breathless (Btl; FGFR2_DROME, Q09147; FlyBase FBgn0285896; GeneID 39564) is one of the two
  Drosophila FGF receptors; the other is Heartless (Htl). It is a 1052-aa single-pass type I
  membrane protein with a signal peptide (1-19), an extracellular region with five Ig-like C2
  domains (23-585), a transmembrane helix (601-626) and a cytoplasmic split tyrosine kinase domain
  (712-1000) [UniProt Q09147 FT lines]. UniProt: "Belongs to the protein kinase superfamily. Tyr
  protein kinase family. Fibroblast growth factor receptor subfamily."
• Original cloning: PMID:1849109, and
  PMID:1325393.

Ligand and signalling mechanism

• Ligand is Branchless (Bnl), an FGF homolog: PMID:8978613.
• Bnl binds Btl at the recipient cell surface; endogenous tagged ligand and receptor colocalize
  PMID:30328809; Btl is on cytonemes that contact the Bnl source
  PMID:21493861.
• Signal transduction requires the FGFR-specific adaptor Dof/Stumps/Heartbroken, which forms a
  complex with activated Btl and is tyrosine phosphorylated, then recruits Csw (SHP2) to activate
  Ras/MAPK [PMID:15082772 "expression of constitutive active Btl or Htl led to strong tyrosine
  phosphorylation of Dof"; "full-length Dof or the minimal Dof600 protein formed a complex with the
  activated version of both Drosophila FGFRs upon induction"]; PMID:9809073; [PMID:9778498 heartbroken "acts downstream of the two FGF receptors but either
  upstream of or parallel to RAS1"]; Src64B also binds phospho-Dof PMID:20154139.
• The intracellular domain mainly supplies a generic RTK signal: PMID:11714681.
• btl transcription is positively fed back by Bnl/Btl–MAPK signalling PMID:12175485. Surface level is controlled by
  endocytic machinery (Hrs/Stam, dVHL) [PMID:20422006; PMID:20516215].

Biological roles

Embryonic tracheal system (core)

• Required for tracheal cell migration and primary branch formation: PMID:1325393; temporal
  requirement at onset of migration and for tracheole (terminal branch) formation PMID:8541215.
• Graded activity patterns secondary and terminal branch fates PMID:8918892; required to activate secondary
  branching markers PMID:8625828.
• Tip (lead) cell selection by competition in FGFR activity PMID:16760977.
• FGF acts as a chemoattractant read by individual cells PMID:26342211.
• Filopodial activity of tip cells PMID:12015974; FGF-dependent extensions contacting bridge-cells for branch interconnection
  PMID:12034756.
• Tracheal invagination itself does not need btl PMID:1849109 – relevant to the GO:0035202 tracheal pit formation annotation (PMID:16818611, abstract
  only, which is about Crossveinless-c and EGFR).

Larval/pupal trachea

• Air sac primordium (ASP): FGF is mitogen and chemoattractant PMID:12194851; Fgf directs migration
  at the tip PMID:16326394; Bnl/Btl induces Vein via Pnt PMID:26632449; proliferation vs
  endoreplication of tracheal progenitors PMID:31237953.
• Terminal cells: activated Btl (λBtl) increases branching and cell growth PMID:21750259 and
  ectopic lumen formation, dependent on Zpr1 [PMID:23029159 "overexpression of this activated form of
  the FGFR in terminal cells resulted in increased lumen formation"; loss-of-function could not be
  tested "because tracheal cells mutant for btl fail to outgrow or undergo branching"].

Other tissues (non-core)

• Midline glia migration in embryo PMID:1325393; retinal basal glia in eye disc, where Btl
  restricts the onset/extent of migration PMID:22384378.
• Border cell migration in ovary: btl is a target of Slbo/C/EBP and genetically enhances slbo
  PMID:7671793.
• Male genital disc: FGF recruits mesodermal cells expressing its receptor PMID:12062107.
• Adult brain dorsal cluster neuron axon retraction PMID:17032066.
• Lymph gland progenitor maintenance via vascular-niche Bnl PMID:33395389; lamellocyte Btl in wasp
  egg melanization PMID:32396065.
• NMJ: btl heterozygosity enhances Smn knockdown NMJ defects, but has no effect alone
  PMID:21300852.