phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing alpha (PIK3C2A)

Function

• phosphorylates PtdIns, PtdIns4P & PtdIns(4,5)P2
• may play a role in:
  • clathrin-coated endocytic vesicle formation
  • EGF signaling cascade
  • mitosis
  • UV-induced damage response
  • insulin signaling
• part of a complex with ERBB2 & EGFR
• interacts with clathrin trimers
• activated by insulin (putative)
• only slightly inhibited by wortmannin & LY294002
• activated by clathrin
• phosphorylated upon insulin stimulation; which may lead to enzyme activation (putative)
• phosphorylated on Ser-259 during mitosis & upon UV irradiation, which does not change enzymatic activity but leads to proteasomal degradation
• Ser-259 phosphorylation may be mediated by CDC2 or JNK, depending on the physiological state of the cell

ATP + 1-phosphatidyl-1D-myo-inositol 4-phosphate
                   <-->
ADP + 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate

Cofactor: Ca+2 or Mg+2, Mn+2 cannot be used

Kinetic parameters:

• KM=122 uM for Ptdins (in the absence of phosphatidylserine)
• KM=64 uM for Ptdins (in the presence of phosphatidylserine)
• KM=25 uM for Ptdins4P (in the presence of phosphatidylserine)
• KM=15 uM for ATP (with Ptdins as substrate) (in the absence of phosphatidylserine)
• KM=32 uM for ATP (with Ptdins as substrate) (in the presence of phosphatidylserine)
• KM=54 uM for ATP (with Ptdins4P as substrate) (in the presence of phosphatidylserine)
• Vmax=990 pmol/min/mg enzyme with Ptdins as substrate (in the absence of phosphatidylserine)
• Vmax=200 pmol/min/mg enzyme with Ptdins as substrate (in the presence of phosphatidylserine)
• Vmax=240 pmol/min/mg enzyme with Ptdins4P as substrate (in the presence of phosphatidylserine)
• Vmax=6800 pmol/min/mg enzyme toward ATP with Ptdins as substrate (in the absence of phosphatidylserine)
• Vmax=805 pmol/min/mg enzyme toward ATP with Ptdins as substrate (in the presence of phosphatidylserine)
• Vmax=880 pmol/min/mg enzyme toward ATP with Ptdins4P as substrate (in the presence of phosphatidylserine)

Structure

• belongs to the PI3/PI4-kinase family
• contains 1 C2 domain
• contains 1 PI3K/PI4K domain
• contains 1 PX (phox homology) domain

Compartment

• cell membrane, Golgi, cytoplasmic vesicle, clathrin-coated vesicle, nucleus, cytoplasm

Expression

• expressed in columnar & transitional epithelia, mononuclear cells, smooth muscle cells, & endothelial cells lining capillaries & small venules (at protein level)
• ubiquitously expressed
• highest levels in heart, placenta & ovary
• lowest levels in kidney

Notes

• in the absence of the carrier phosphatidylserine, enzymatic kinetics toward Ptdins4P are non-linear

More general terms

• phosphatidylinositol-4-phosphate 3-kinase

Database

• OMIM: https://mirror.omim.org/entry/603601
• UniProt: http://www.uniprot.org/uniprot/O00443.html