View source for Protein phosphatase 2

{{redirect|PP2|the kinase inhibitor|PP2 (kinase inhibitor)|the movie|The Pink Panther 2}}
{{infobox protein
|Name=[[PPP2CA|protein phosphatase 2, catalytic subunit, alpha isoform]]
|caption=The catalytic (C) subunit of protein phosphatase 2A. The protein is shown in rainbow color with the [[N-terminus]] in blue and the [[C-terminus]] in red. The [[methylated]] [[carboxyl group]] of the C-terminal [[leucine]] residue is shown in white. The purple spheres are two catalytically required [[manganese]] ions and the dark gray compound at center is a peptidomimetic toxin, [[microcystin]], occupying the [[active site]]. From {{PDB|2IAE}}.<ref name="cho_2006">{{cite journal | vauthors = Cho US, Xu W | title = Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme | journal = Nature | volume = 445 | issue = 7123 | pages = 53–7 | date = January 2007 | pmid = 17086192 | doi = 10.1038/nature05351 }}</ref> 
|image=Pp2a 2iae chainCM.png 
|width=
|HGNCid=9299
|Symbol=[[PPP2CA]]
|AltSymbols=
|EntrezGene=5515
|OMIM=176915
|RefSeq=NM_002715
|UniProt=P67775
|PDB=
|ECnumber=3.1.3.16
|Chromosome=5
|Arm=q
|Band=23
|LocusSupplementaryData=-q31
}}
{{infobox protein
| Name = [[PPP2CB|protein phosphatase 2, catalytic subunit, beta isoform]]
| caption = 
| image = 
| width = 
| HGNCid = 9300
| Symbol = [[PPP2CB]]
| AltSymbols = 
| EntrezGene = 5516
| OMIM = 176916
| RefSeq = NM_001009552
| UniProt = P62714
| PDB = 
| ECnumber = 3.1.3.16
| Chromosome = 8
| Arm = p
| Band = 12
| LocusSupplementaryData = 
}}
'''Protein phosphatase 2 '''('''PP2'''), also known as '''PP2A''', is an [[enzyme]] that in humans is encoded by the ''PPP2CA'' [[gene]].<ref name="pmid8383590">{{cite journal | vauthors = Jones TA, Barker HM, da Cruz e Silva EF, Mayer-Jaekel RE, Hemmings BA, Spurr NK, Sheer D, Cohen PT | title = Localization of the genes encoding the catalytic subunits of protein phosphatase 2A to human chromosome bands 5q23→q31 and 8p12→p11.2, respectively | journal = Cytogenetics and Cell Genetics | volume = 63 | issue = 1 | pages = 35–41 | year = 1993 | pmid = 8383590 | doi = 10.1159/000133497 }}</ref> The PP2A [[Heterotrimeric G protein|heterotrimeric]] [[protein phosphatase]] is ubiquitously expressed, accounting for a large fraction of phosphatase activity in [[Eukaryote|eukaryotic]] cells.<ref name="pmid17632053">{{cite journal | vauthors=Mumby M | title=PP2A: unveiling a reluctant tumor suppressor | journal= [[Cell (journal)|Cell]] | volume=130 | issue=1 | pages=21–24 | year=2007 |url=http://www.cell.com/cell/fulltext/S0092-8674(07)00839-2 | DOI=10.1016/j.cell.2007.06.034 | PMID = 17632053 }}</ref> Its [[Protein serine/threonine phosphatase|serine/threonine phosphatase]] activity has a broad substrate specificity and diverse cellular functions. Among the targets of PP2A are proteins of oncogenic signaling cascades, such as [[c-Raf|Raf]], [[Mitogen-activated protein kinase kinase|MEK]], and [[AKT]], where PP2A may act as a tumor suppressor.

== Structure and function ==
PP2A consists of a dimeric core enzyme composed of the structural A and catalytic C subunits, and a regulatory B subunit. When the PP2A catalytic C subunit associates with the A and B subunits several species of holoenzymes are produced with distinct functions and characteristics.  The A subunit, a founding member of the [[HEAT repeat domain|HEAT repeat protein family]] (huntington-elongation-A subunit-TOR), is the scaffold required for the formation of the heterotrimeric complex.  When the A subunit binds it alters the enzymatic activity of the catalytic subunit, even if the B subunit is absent.  While C and A subunit sequences show remarkable sequence conservation throughout eukaryotes, regulatory B subunits are more heterogeneous and are believed to play key roles in controlling the localization and specific activity of different holoenzymes. Multicellular [[eukaryote]]s express four classes of variable regulatory subunits: B (PR55), B′ (B56 or PR61), B″ (PR72), and B‴ (PR93/PR110), with at least 16 members in these subfamilies. In addition, accessory proteins and posttranslational modifications (such as methylation) control PP2A subunit associations and activities.

The two catalytic metal ions located in PP2A's [[active site]] are [[manganese]].<ref name=cho_2006 />

{| class="wikitable"
|-
! Function !! Protein !! Description !! Note
|-
| rowspan="2" | Structural subunit A || [[PPP2R1A]] || PP2A 65 kDa regulatory subunit A alpha isoform  || subunit A, PR65-alpha isoform
|-
| [[PPP2R1B]] || PP2A 65 kDa regulatory subunit A beta isoform   || subunit A, PR65-beta isoform
|-
| rowspan="13" | Regulatory subunit B || [[PPP2R2A]] || PP2A 55 kDa regulatory subunit B alpha isoform   || subunit A, B-alpha isoform
|-
| [[PPP2R2B]] || PP2A 55 kDa regulatory subunit B beta isoform  || subunit B, B-beta isoform
|-
| [[PPP2R2C]] || PP2A 55 kDa regulatory subunit B gamma isoform  || subunit B, B-gamma isoform
|-
| [[PPP2R2D]] || PP2A 55 kDa regulatory subunit B delta isoform  || subunit B, B-delta isoform
|-
| [[PPP2R3A]] || PP2A 72/130 kDa regulatory subunit B               || subunit B, B<nowiki>''</nowiki>-PR72/PR130
|-
| [[PPP2R3B]] || PP2A 48 kDa regulatory subunit B                  || subunit B, PR48 isoform
|-
| [[PPP2R3C]] || PP2A regulatory subunit B<nowiki>''</nowiki> subunit gamma                  || subunit G5PR
|-
| [[PPP2R4]]  || PP2A regulatory subunit B'                      || subunit B', PR53 isoform
|-
| [[PPP2R5A]] || PP2A 56 kDa regulatory subunit alpha isoform    || subunit B, B' alpha isoform
|-
| [[PPP2R5B]] || PP2A 56 kDa regulatory subunit beta isoform     || subunit B, B' beta isoform
|-
| [[PPP2R5C]] || PP2A 56 kDa regulatory subunit gamma isoform    || subunit B, B' gamma isoform
|-
| [[PPP2R5D]] || PP2A 56 kDa regulatory subunit delta isoform    || subunit B, B' delta isoform
|-
| [[PPP2R5E]] || PP2A 56 kDa regulatory subunit epsilon isoform  || subunit B, B' epsilon isoform
|-
| rowspan="2" | Catalytic subunit C || [[PPP2CA]] || catalytic subunit alpha isoform
|-
| [[PPP2CB]] || catalytic subunit beta isoform
|-
|}

[[File:Pp2a 2iae chainABC 1b3u chainA.png|thumb|right|The assembled heterotrimer of protein phosphatase 2A. The structural subunit A, consisting of 15 [[HEAT repeat]]s, is shown in rainbow color with the N-terminus in blue at bottom and the C-terminus in red at top. The regulatory subunit B, consisting of irregular pseudo-HEAT repeats, is shown in light blue. The catalytic subunit C is shown in tan. (All from {{PDB|2IAE}}.) Superposed is the unbound form of the regulatory subunit A in gray (from {{PDB|1B3U}}), illustrating the flexibility of this [[alpha solenoid]] protein. Conformational changes in HEAT repeat 11 result in flexing the C-terminal end of the protein to accommodate binding of the catalytic subunit.<ref name=cho_2006 /><ref name="groves_1999">{{cite journal | vauthors = Groves MR, Hanlon N, Turowski P, Hemmings BA, Barford D | title = The structure of the protein phosphatase 2A PR65/A subunit reveals the conformation of its 15 tandemly repeated HEAT motifs | journal = Cell | volume = 96 | issue = 1 | pages = 99–110 | date = January 1999 | pmid = 9989501 | doi = 10.1016/S0092-8674(00)80963-0 }}</ref>]]

== Drug discovery ==
PP2 has been identified as a potential [[biological target]] to discover drugs to treat [[Parkinson's disease]] and [[Alzheimer's disease]], however as of 2014 it was unclear which isoforms would be most beneficial to target, and also whether activation or inhibition would be most therapeutic.<ref name="pmid22342821">{{cite journal | vauthors = Braithwaite SP, Voronkov M, Stock JB, Mouradian MM | title = Targeting phosphatases as the next generation of disease modifying therapeutics for Parkinson's disease | journal = Neurochemistry International | volume = 61 | issue = 6 | pages = 899–906 | date = November 2012 | pmid = 22342821 | doi = 10.1016/j.neuint.2012.01.031 }}</ref><ref name="pmid24653673">{{cite journal | vauthors = Sontag JM, Sontag E | title = Protein phosphatase 2A dysfunction in Alzheimer's disease | journal = Frontiers in Molecular Neuroscience | volume = 7 | issue =  | pages = 16 | year = 2014 | pmid = 24653673 | pmc = 3949405 | doi = 10.3389/fnmol.2014.00016 }}</ref>

PP2 has also been identified as a [[Tumor suppressor gene|tumor suppressor]] for [[Tumors of the hematopoietic and lymphoid tissues|blood cancers]], and as of 2015 programs were underway to identify compounds that could either directly activate it, or that could inhibit other proteins that suppress its activity.<ref name="pmid25763353">{{cite journal | vauthors = Ciccone M, Calin GA, Perrotti D | title = From the Biology of PP2A to the PADs for Therapy of Hematologic Malignancies | journal = Frontiers in Oncology | volume = 5 | issue =  | pages = 21 | year = 2015 | pmid = 25763353 | pmc = 4329809 | doi = 10.3389/fonc.2015.00021 }}</ref>

== References ==
{{Reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Seshacharyulu P, Pandey P, Datta K, Batra SK | title = Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer | journal = Cancer Letters | volume = 335 | issue = 1 | pages = 9–18 | date = July 2013 | pmid = 23454242 | pmc = 3665613 | doi = 10.1016/j.canlet.2013.02.036 }}
* {{cite journal | vauthors = Xu Y, Xing Y, Chen Y, Chao Y, Lin Z, Fan E, Yu JW, Strack S, Jeffrey PD, Shi Y | title = Structure of the protein phosphatase 2A holoenzyme | journal = Cell | volume = 127 | issue = 6 | pages = 1239–51 | date = December 2006 | pmid = 17174897 | doi = 10.1016/j.cell.2006.11.033 }}
* {{cite journal | vauthors = Xing Y, Xu Y, Chen Y, Jeffrey PD, Chao Y, Lin Z, Li Z, Strack S, Stock JB, Shi Y | title = Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins | journal = Cell | volume = 127 | issue = 2 | pages = 341–53 | date = October 2006 | pmid = 17055435 | doi = 10.1016/j.cell.2006.09.025 }}
* {{cite journal | vauthors = Ory S, Zhou M, Conrads TP, Veenstra TD, Morrison DK | title = Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites | journal = Current Biology | volume = 13 | issue = 16 | pages = 1356–64 | date = August 2003 | pmid = 12932319 | doi = 10.1016/S0960-9822(03)00535-9 }}
{{refend}}

== External links ==
* {{MeshName|PPP2CA+protein,+human}}

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[[Category:Human proteins]]
[[Category:EC 3.1.3]]