Pik3c2a (rat, D3ZTF6) - manual literature synthesis

No deep-research API was available for this review. This file records a manual
literature survey done with PubMed searches and the cached publications in
publications/. Quotes are verbatim from the cached files.

Identity

• Rat Pik3c2a, UniProtKB D3ZTF6 (TrEMBL, unreviewed, 1687 aa), RGD:1310389,
  GeneID 361632. PE level 3 (inferred from homology). Ortholog of human
  PIK3C2A (O00443) and mouse Pik3c2a (Q61194, MGI:1203729).
• Domain architecture (InterPro/Pfam in the UniProt record): Ras-binding domain
  (PF00794), C2 (PI3K-type, PF00792), PI3K helical/accessory (PF00613),
  PI3/PI4 kinase catalytic domain (PF00454), PX domain (PF00787) and C-terminal
  C2 domain (PF00168); InterPro IPR037705 "PI3-kinase_C2-alpha_cat" and
  IPR042133 "PX_PI3K_C2_alpha". The catalytic loop (DRHNDN, residue 1251) and
  DFG motif (residue 1269) are present in the rat sequence; the C2-domain
  nuclear localisation stretch KRKTKISRKTR mapped in the human protein
  (PMID:11606566) is conserved at residue 1610.

Catalytic activity and lipid products

• Human PI3K-C2alpha cloning: PMID:9337861 and it is refractory
  to wortmannin/LY294002.
• In vivo product during insulin signalling is PI3P: PMID:17644513.
• At clathrin-coated pits it generates PI(3,4)P2: PMID:23823722.
• Clathrin binds the N-terminus and activates the kinase: PMID:11239472.
  The clathrin-binding domain alone drives lattice assembly PMID:16215232.
• The PX domain binds PI(4,5)P2 and mediates membrane recruitment
  PMID:17038310.

Localisation

• Rat brain clathrin-coated vesicles PMID:10766823; perinuclear TGN staining with
  gamma-adaptin and TGN-46 in the same paper.
• Coated pits at the plasma membrane PMID:11239472.
• Nucleus/nuclear speckles in HeLa cells PMID:11606566.
• Pericentriolar recycling endosome at the cilium base PMID:24697898.
• Mature secretory granules in PC12 (rat) cells PMID:16055506.

Rat-specific experimental evidence

• PC12 (rat pheochromocytoma) cells: PMID:16055506 (abstract only in cache).
• INS1 rat insulinoma cells (key paper, full text read): PMID:21127054. Calcium
  influx was unaffected, KCl-evoked secretion did not need insulin receptor or
  Akt, and SNAP25 proteolysis was reduced, placing the defect at granule
  fusion. Both stable shRNA and transient siRNA lines were used. This is
  knockdown (phenotype) evidence; the mechanistic inference is that
  PI3K-C2alpha-derived PtdIns3P is needed for fusion competence, as in PC12
  cells.
• Rat brain CCV fractionation (PMID:10766823, above).

Endocytosis and trafficking

• Clathrin-mediated endocytosis: depletion impairs late-stage coated-pit
  maturation and SNX9 recruitment PMID:23823722.
• Dynamin-independent uptake PMID:21081650.
• Endothelial endosomal trafficking and VE-cadherin delivery; the global and
  endothelial knockout is embryonic lethal with angiogenesis defects
  PMID:22983395.
• Rab11 activation and ciliogenesis PMID:24697898; human loss-of-function
  causes a syndromic ciliopathy-like disorder PMID:31034465.

Autophagy

• Mouse MEFs, combined class II alpha+beta siRNA: PMID:24098492
• Human U2OS cells: PMID:28910396
• Kidney epithelia, shear stress: PMID:32102612

Signalling

• Insulin: recruitment to the plasma membrane via TC10, contributes to GLUT4
  translocation (PMID:17644513). In beta cells, knockdown reroutes IR-B
  signalling from PKB to ERK (PMID:26387957). In INS1 cells KCl-evoked
  secretion is Akt-independent (PMID:21127054).
• Class II PI3K-C2alpha makes PI3P and PI(3,4)P2 rather than PIP3, so the
  class I PI3K/PKB axis is not its core output.

Other

• Podocyte/glomerular maintenance in knockout mice (PMID:20974805).
• Mitotic spindle scaffolding function independent of kinase activity
  (PMID:29017056, abstract only, not used for annotation).
• miR-206 targets PIK3C2A in endothelial progenitor cells (PMID:26175229).