Recombinant Human Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PPP2CA)

Function

Catalytic subunit of protein phosphatase 2A (PP2A), a serine/threonine phosphatase involved in the regulation of a wide variety of enzymes, signal transduction pathways, and cellular events (PubMed:10801873, PubMed:12473674, PubMed:17245430, PubMed:22613722, PubMed:33243860, PubMed:34004147, PubMed:9920888). PP2A is the major phosphatase for microtubule-associated proteins (MAPs) (PubMed:22613722). PP2A can modulate the activity of phosphorylase B kinase casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2 kinase (PubMed:22613722). Cooperates with SGO2 to protect centromeric cohesin from separase-mediated cleavage in oocytes specifically during meiosis I (By similarity). Can dephosphorylate various proteins, such as SV40 large T antigen, AXIN1, p53/TP53, PIM3, WEE1 (PubMed:10801873, PubMed:12473674, PubMed:17245430, PubMed:9920888). Activates RAF1 by dephosphorylating it at 'Ser-259' (PubMed:10801873). Mediates dephosphorylation of WEE1, preventing its ubiquitin-mediated proteolysis, increasing WEE1 protein levels, and promoting the G2/M checkpoint (PubMed:33108758). Mediates dephosphorylation of MYC; promoting its ubiquitin-mediated proteolysis: interaction with AMBRA1 enhances interaction between PPP2CA and MYC (PubMed:25438055). Mediates dephosphorylation of FOXO3; promoting its stabilization: interaction with AMBRA1 enhances interaction between PPP2CA and FOXO3 (PubMed:30513302). Catalyzes dephosphorylation of the pyrin domain of NLRP3, promoting assembly of the NLRP3 inflammasome (By similarity). Together with RACK1 adapter, mediates dephosphorylation of AKT1 at 'Ser-473', preventing AKT1 activation and AKT-mTOR signaling pathway (By similarity). Dephosphorylation of AKT1 is essential for regulatory T-cells (Treg) homeostasis and stability (By similarity). Catalyzes dephosphorylation of PIM3, promoting PIM3 ubiquitination and proteasomal degradation (PubMed:12473674). Part of the striatin-interacting phosphatase and kinase (STRIPAK) complexes (PubMed:33633399). STRIPAK complexes have critical roles in protein (de)phosphorylation and are regulators of multiple signaling pathways including Hippo, MAPK, nuclear receptor and cytoskeleton remodeling (PubMed:33633399). Different types of STRIPAK complexes are involved in a variety of biological processes such as cell growth, differentiation, apoptosis, metabolism and immune regulation (PubMed:33633399). Key mediator of a quality checkpoint during transcription elongation as part of the Integrator-PP2A (INTAC) complex (PubMed:33243860, PubMed:34004147, PubMed:37080207). The INTAC complex drives premature transcription termination of transcripts that are unfavorably configured for transcriptional elongation: within the INTAC complex, PPP2CA catalyzes dephosphorylation of the C-terminal domain (CTD) of Pol II subunit POLR2A/RPB1 and SUPT5H/SPT5, thereby preventing transcriptional elongation (PubMed:33243860, PubMed:34004147, PubMed:37080207)

Subcellular Location

Cytoplasm; Nucleus; Chromosome; Chromosome, centromere; Cytoplasm, cytoskeleton, spindle pole

Disease Association

Houge-Janssens syndrome 3 (HJS3) : An autosomal dominant neurodevelopmental disorder characterized by global developmental delay with onset in infancy and additional variable features including hypotonia, epilepsy, brain abnormalities such as ventriculomegaly and a small corpus callosum, and autism spectrum disorder. [The disease is caused by variants affecting the gene represented in this entry]

Subunit

PP2A consists of a common heterodimeric core enzyme composed of PPP2CA, a 36 kDa catalytic subunit (subunit C), and PPP2R1A, a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits (PubMed:17055435, PubMed:18394995, PubMed:30595372, PubMed:38123684). Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules (PubMed:18394995, PubMed:30595372, PubMed:38123684). Interacts with the PP2A A subunit PPP2R1A (PubMed:37761890, PubMed:38123684). Interacts with the regulatory subunit PPP2R2A (PubMed:38123684). Interacts (via C-terminus) with PTPA (PubMed:25003389). Interacts with NXN; the interaction is direct (By similarity). Interacts with KCTD20 (By similarity). Interacts with BTBD10 (By similarity). Interacts with SGO1 and SGO2 (PubMed:16541025, PubMed:16580887, PubMed:17485487). Interacts with RAF1 (PubMed:10801873). Interaction with IGBP1 protects unassembled PPP2CA from degradative ubiquitination (PubMed:19818709, PubMed:20092282, PubMed:9647778). Interacts with GSK3B (via C2 domain) (PubMed:20080667). Interacts with MFHAS1; retains PPP2CA into the cytoplasm and excludes it from the nucleus (PubMed:28609714). Interacts with PABIR1/FAM122A (PubMed:27588481, PubMed:38123684). Interacts with ADCY8; interaction is phosphatase activity-dependent; antagonizes interaction between ADCY8 and calmodulin (PubMed:16258073). Interacts with CRTC3 (when phosphorylated at 'Ser-391') (PubMed:30611118). Interacts with SPRY2; the interaction is inhibited by TESK1 interaction with SPRY2, possibly by vesicular sequestration of SPRY2 (PubMed:17974561). Interacts with TRAF3IP3 (PubMed:30115741). Interacts with AMBRA1 (via PxP motifs); enhancing interaction between PPP2CA and MYC or FOXO3 (PubMed:25438055, PubMed:30513302). Forms a complex with AMBRA1 and BECN1; AMBRA1 and BECN1 components of the complex regulate MYC stability via different pathways (PubMed:25803737). Part of the core of STRIPAK complexes composed of PP2A catalytic and scaffolding subunits, the striatins (PP2A regulatory subunits), the striatin-associated proteins MOB4, STRIP1 and STRIP2, PDCD10 and members of the STE20 kinases, such as STK24 and STK26 (PubMed:33633399). Phosphatase component of the Integrator-PP2A (INTAC) complex, composed of the Integrator core complex and protein phosphatase 2A subunits PPP2CA and PPP2R1A (PubMed:33243860, PubMed:34004147, PubMed:37080207, PubMed:34762484, PubMed:36869814, PubMed:38570683)

• Stone S.R. et al. The nucleotide sequence of the cDNA encoding the human lung protein phosphatase 2A alpha catalytic subunit. — Nucleic Acids Res. (1988)
• Arino J. et al. Human liver phosphatase 2A: cDNA and amino acid sequence of two catalytic subunit isotypes. — Proc. Natl. Acad. Sci. U.S.A. (1988)
• Khew-Goodall Y. et al. Structure and transcriptional regulation of protein phosphatase 2A catalytic subunit genes. — Biochemistry (1991)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Scheidtmann K.H. et al. Dephosphorylation of simian virus 40 large-T antigen and p53 protein by protein phosphatase 2A: inhibition by small-t antigen. — Mol. Cell. Biol. (1991)
• Favre B. et al. The catalytic subunit of protein phosphatase 2A is carboxyl-methylated in vivo. — J. Biol. Chem. (1994)
• Chen J. et al. Alpha 4 associates with protein phosphatases 2A, 4, and 6. — Biochem. Biophys. Res. Commun. (1998)
• Bryant J.C. et al. Methylated C-terminal leucine residue of PP2A catalytic subunit is important for binding of regulatory Balpha subunit. — Biochem. J. (1999)