The phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (the

HUGO Hugo or HUGO may refer to: Arts and entertainment * ''Hugo'' (film), a 2011 film directed by Martin Scorsese * Hugo Award, a science fiction and fantasy award named after Hugo Gernsback * Hugo (franchise), a children's media franchise based on ...

-approved official symbol = PIK3CA; HGNC ID, HGNC:8975), also called p110α protein, is a

class I PI 3-kinase Class I PI 3-kinases are a subgroup of the enzyme family, phosphoinositide 3-kinase that possess a common protein domain structure, substrate specificity, and method of activation. Class I PI 3-kinases are further divided into two subclasses, class ...

catalytic subunit. The human p110α protein is encoded by the ''PIK3CA'' gene. Its role was uncovered by

molecular pathological epidemiology Molecular pathological epidemiology (MPE, also molecular pathologic epidemiology) is a discipline combining epidemiology and pathology. It is defined as "epidemiology of molecular pathology and heterogeneity of disease". Pathology and epidemiology s ...

(MPE).

Function

Phosphatidylinositol-4,5-bisphosphate 3-kinase In enzymology, a phosphatidylinositol-4,5-bisphosphate 3-kinase () is an enzyme that catalyzes the chemical reaction: :ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate \rightleftharpoons ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphospha ...

(also called

phosphatidylinositol 3-kinase Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...

(PI3K)) is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate

phosphatidylinositol Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...

s (PtdIns), PtdIns4P and

PtdIns(4,5)P2 Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number of ...

. The involvement of p110α in human cancer has been hypothesized since 1995. Support for this hypothesis came from genetic and functional studies, including the discovery of common activating PIK3CA missense mutations in common human tumors. It has been found to be

oncogenic Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...

and is implicated in cervical cancers. ''PIK3CA'' mutations are present in over one-third of breast cancers, with enrichment in the luminal and in human epidermal growth factor receptor 2-positive subtypes (HER2 +). The three hotspot mutation positions (GLU542, GLU545, and HIS1047) have been widely reported till date. While substantial preclinical data show an association with robust activation of the pathway and resistance to common therapies, clinical data do not indicate that such mutations are associated with high levels of pathway activation or with a poor prognosis. It is unknown whether the mutation predicts increased sensitivity to agents targeting the P3K pathway. PIK3CA participates in a complex interaction within the

tumor microenvironment The tumor microenvironment (TME) is the environment around a tumor, including the surrounding blood vessels, immune cells, fibroblasts, signaling molecules and the extracellular matrix (ECM). The tumor and the surrounding microenvironment are cl ...

in this phenomenon.

Clinical characteristics

Due to the association between p110α and cancer, it may be an appropriate drug target. Pharmaceutical companies are designing and characterizing potential p110α isoform specific inhibitors. The presence of PIK3CA mutation may predict response to aspirin therapy for colorectal cancer. Somatic activating mutations in PIK3CA are found in

Klippel–Trénaunay syndrome Klippel–Trénaunay syndrome, formerly Klippel–Trénaunay–Weber syndrome and sometimes angioosteohypertrophy syndrome and hemangiectatic hypertrophy, is a rare congenital medical condition in which blood vessels and/or lymph vessels fail to ...

and

venous malformation A vascular malformation is a blood vessel or lymph vessel vascular anomalies, abnormality. Vascular malformations are one of the classifications of vascular anomaly, vascular anomalies, the other grouping is vascular tumors. They may cause aestheti ...

. ''PIK3CA''-associated segmental overgrowth includes brain disorders such as

macrocephaly-capillary malformation Macrocephaly-capillary malformation (M-CM) is a multiple malformation syndrome causing abnormal body and head overgrowth and cutaneous, vascular, neurologic, and limb abnormalities. Though not every patient has all features, commonly found signs ...

(MCAP) and

hemimegalencephaly Hemimegalencephaly (HME), or unilateral megalencephaly, is a rare congenital disorder affecting all or a part of a cerebral hemisphere. It causes severe seizures, which are often frequent and hard to control. A minority might have seizure contro ...

. It is also associated with congenital, lipomatous overgrowth of vascular malformations, epidermal nevi and skeletal/spinal anomalies (

CLOVES syndrome CLOVES syndrome is a rare overgrowth syndrome with complex vascular anomalies. CLOVES syndrome affects people with various symptoms, ranging from mild fatty soft-tissue tumors to vascular malformations encompassing the spine or internal organs. It ...

) and fibroadipose

hyperplasia Hyperplasia (from ancient Greek ὑπέρ ''huper'' 'over' + πλάσις ''plasis'' 'formation'), or hypergenesis, is an enlargement of an organ or tissue caused by an increase in the amount of organic tissue that results from cell proliferati ...

(FH). The conditions are caused by heterozygous (usually somatic mosaic) mutations.

Inhibition

All PI 3-kinases are inhibited by the drugs

wortmannin Wortmannin, a steroid metabolite of the fungi ''Penicillium funiculosum'', '' Talaromyces wortmannii'', is a non-specific, covalent inhibitor of phosphoinositide 3-kinases (PI3Ks). It has an ''in vitro'' inhibitory concentration (''IC''50) of a ...

and

LY294002 LY294002 is a morpholine-containing chemical compound that is a potent inhibitor of numerous proteins, and a strong inhibitor of phosphoinositide 3-kinases (PI3Ks). It is generally considered a non-selective research tool, and should not be used ...

but wortmannin shows better efficiency than LY294002 on the hotspot mutation positions.

Pharmacology

In September 2017

Copanlisib Copanlisib (trade name Aliqopa ; codenamed BAY 80-6946) is a drug which is approved by US FDA for the treatment of adult patients experiencing relapsed follicular lymphoma who have received at least two prior systemic therapies. Copanlisib has ...

, inhibiting predominantly p110α and p110δ, got

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

approval for the treatment of adult patients with relapsed

follicular lymphoma Follicular lymphoma (FL) is a cancer that involves certain types of white blood cells known as lymphocytes. The cancer originates from the uncontrolled division of specific types of B-cells known as centrocytes and centroblasts. These cells normal ...

(FL) who have received at least two prior systemic therapies.

Interactions

P110α has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with: *

ARHGEF1 Rho guanine nucleotide exchange factor 1 is a protein that in humans is encoded by the ''ARHGEF1'' gene. This protein is also called RhoGEF1 or p115-RhoGEF. Function Rho guanine nucleotide exchange factor 1 is guanine nucleotide exchange fac ...

, * ADAP1, * DGKZ, *

HRAS GTPase HRas, from "Harvey Rat sarcoma virus", also known as transforming protein p21 is an enzyme that in humans is encoded by the gene. The ''HRAS'' gene is located on the short (p) arm of chromosome 11 at position 15.5, from base pair 522,241 t ...

, and *

Lck Lck (or lymphocyte-specific protein tyrosine kinase) is a 56 kDa protein that is found inside specialized cells of the immune system called lymphocytes. The Lck is a member of Src kinase family (SFK), it is important for the activation of the T ...

Function

Clinical characteristics

Inhibition

Pharmacology

See also

Interactions

References

Further reading