View source for PHLPP

{{Short description|Class of enzymes}}
{{infobox protein
| Name = [[PHLPP (gene)|PH domain and leucine-rich repeat protein phosphatase]]
| caption =
| image =
| width =
| HGNCid = 20610
| Symbol = [[PHLPP (gene)|PHLPP]]
| AltSymbols = PHLPP1, PLEKHE1
| EntrezGene = 23239
| OMIM = 609396
| RefSeq = XM_166290
| UniProt = O60346
| PDB =
| ECnumber = 3.1.3.16
| Chromosome = 18
| Arm = q
| Band = 21.32
| LocusSupplementaryData =
}}
{{infobox protein
| Name = [[PHLPPL|PH domain and leucine rich repeat protein phosphatase-like]]
| caption =
| image =
| width =
| HGNCid = 29149
| Symbol = [[PHLPPL]]
| AltSymbols = PHLPP2
| EntrezGene = 23035
| OMIM = 611066
| RefSeq = NM_015020
| UniProt = Q6ZVD8
| PDB =
| ECnumber = 3.1.3.16
| Chromosome = 16
| Arm = q
| Band = 22.2
| LocusSupplementaryData =
}}
The '''PHLPP'''  isoforms ('''PH domain and Leucine rich repeat Protein Phosphatases''') are a pair of protein [[phosphatase]]s, [[PHLPP (gene)|PHLPP1]] and [[PHLPPL|PHLPP2]], that are important regulators of  [[AKT|Akt]]  serine-threonine kinases ([[AKT1|Akt1]], [[AKT2|Akt2]], [[AKT3|Akt3]]) and conventional/novel [[protein kinase C]] (PKC) isoforms.  PHLPP may act as a tumor suppressor in several types of cancer due to its ability to block growth factor-induced signaling in cancer cells.<ref name="Brognard and Newton, 2008.">{{cite journal |vauthors=Brognard J, Newton AC | title = PHLiPPing the Switch on Akt and Protein Kinase C Signaling | journal = Trends Endocrinol. Metab. | volume = 19 | issue = 6 | pages = 223–30 |date=August 2008 | pmid = 18511290 | pmc = 2963565 | doi = 10.1016/j.tem.2008.04.001 }}</ref>
PHLPP dephosphorylates [[Serine|Ser]]-473 (the hydrophobic motif) in Akt, thus partially inactivating the kinase.<ref name="Gao et al., 2005.">{{cite journal |vauthors=Gao T, Furnari F, Newton AC | title = PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth | journal = Mol. Cell | volume = 18 | issue = 1 | pages = 13–24 |date=April 2005 | pmid = 15808505 | doi = 10.1016/j.molcel.2005.03.008 | doi-access = free }}</ref>
In addition, PHLPP dephosphorylates conventional and novel members of the protein kinase C family at their hydrophobic motifs, corresponding to Ser-660 in PKCβII.<ref name="Gao et al., 2007">{{cite journal |vauthors=Gao T, Brognard J, Newton AC | title = The phosphatase PHLPP controls the cellular levels of protein kinase C | journal = J. Biol. Chem. | volume = 283 | issue = 10 | pages = 6300–11 |date=March 2008 | pmid = 18162466 | doi = 10.1074/jbc.M707319200 | doi-access = free }}</ref>
== Domain structure ==
PHLPP is a member of the PPM family of phosphatases, which requires [[magnesium]] or [[manganese]] for their activity and are insensitive to most common phosphatase inhibitors, including [okadaic acid].  PHLPP1 and PHLPP2 have a similar domain structure, which includes a putative [[Ras (protein)|Ras]] association domain, a [[pleckstrin homology domain]], a series of [[leucine-rich repeat]]s, a PP2C phosphatase domain, and a C-terminal [[PDZ domain|PDZ]] ligand.  PHLPP1 has two splice variants, PHLPP1α and PHLPP1β, of which PHLPP1β is larger by approximately 1.5 kilobase pairs.  PHLPP1α, which was the first PHLPP isoform to be characterized, lacks the [[N-terminus|N-terminal]] portion of the protein, including the Ras association domain.<ref name="Brognard and Newton, 2008." />   PHLPP's domain structure influences its ability to dephosphorylate its substrates.  A PHLPP construct lacking the PH domain is unable to decrease PKC phosphorylation, while PHLPP lacking the PDZ ligand is unable to decrease Akt phosphorylation.<ref name="Gao et al., 2005." />
== Dephosphorylation of Akt==
The phosphatases in the PHLPP family, PHLPP1 and PHLPP2 have been shown to directly dephosphorylate, and therefore inactivate, distinct Akt isoforms, at one of the two critical phosphorylation sites required for activation: Serine473.  PHLPP2 dephosphorylates [[AKT1]] and [[AKT3]], whereas PHLPP1 is specific for [[AKT2]] and AKT3.  Lack of PHLPP appears to have  effects on growth factor-induced Akt phosphorylation.  When both PHLPP1 and PHLPP2 are knocked down using siRNA and cells are stimulated using epidermal growth factor, peak Akt phosphorylation at both Serine473 and Threonine308 (the other site required for full Akt activation) is increased dramatically.<ref name="Brognard et al., 2007.">{{cite journal |vauthors=Brognard J, Sierecki E, Gao T, Newton AC | title = PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms | journal = Mol. Cell | volume = 25 | issue = 6 | pages = 917–31 |date=March 2007 | pmid = 17386267 | doi = 10.1016/j.molcel.2007.02.017 | doi-access = free }}</ref>
=== The Akt family of kinases ===
In humans, there are three genes in the Akt family: [[AKT1]], [[AKT2]], and [[AKT3]]. These [[enzyme]]s are members of the [[Protein kinase#Serine.2Fthreonine specific protein kinases|serine/threonine-specific protein kinase]] family ({{EC number|2.7.11.1}}).
Akt1 is involved in cellular survival pathways and inhibition of [[Apoptosis|apoptotic]]  processes.  Akt1 is also able to induce [[protein synthesis]] pathways, and is therefore a key signaling protein in the cellular pathways that lead to skeletal muscle hypertrophy, and general tissue growth.   Since it can block apoptosis, and thereby promote cell survival, Akt1 has been implicated as a major factor in many types of cancer. Akt (now also called Akt1) was originally identified as the [[oncogene]] in the transforming [[retrovirus]], AKT8.
Akt2 is important in the insulin signaling pathway. It is required to induce glucose transport.{{citation needed|date=February 2019}}
These separate roles for Akt1 and Akt2 were demonstrated by studying mice in which either the Akt1 or the Akt2 gene was deleted, or "knocked out".  In a mouse that is null for Akt1 but normal for Akt2, glucose homeostasis is unperturbed, but the animals are smaller, consistent with a role for Akt1 in growth.  In contrast, mice that do not have Akt2 but have normal Akt1 have mild growth deficiency and display a [[diabetes|diabetic]] phenotype ([[insulin resistance]]), again consistent with the idea that Akt2 is more specific for the [[insulin receptor]] signaling pathway.<ref name="pmid12843127">{{cite journal |vauthors=Garofalo RS, Orena SJ, Rafidi K, Torchia AJ, Stock JL, Hildebrandt AL, Coskran T, Black SC, Brees DJ, Wicks JR, McNeish JD, Coleman KG | title = Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKBβ | journal = J. Clin. Invest. | volume = 112 | issue = 2 | pages = 197–208 |date=July 2003 | pmid = 12843127 | pmc = 164287 | doi = 10.1172/JCI16885 }}</ref>
The role of Akt3 is less clear, though it appears to be expressed predominantly in brain. It has been reported that mice lacking Akt3 have small brains.<ref name="pmid16923958">{{cite journal |vauthors=Dummler B, Tschopp O, Hynx D, Yang ZZ, Dirnhofer S, Hemmings BA | title = Life with a Single Isoform of Akt: Mice Lacking Akt2 and Akt3 Are Viable but Display Impaired Glucose Homeostasis and Growth Deficiencies | journal = Mol. Cell. Biol. | volume = 26 | issue = 21 | pages = 8042–51 |date=November 2006 | pmid = 16923958 | pmc = 1636753 | doi = 10.1128/MCB.00722-06 }}</ref>
=== Phosphorylation of Akt by PDK1 and PDK2 ===
Once correctly positioned in the membrane via binding of [[PIP3]], Akt can then be phosphorylated by its activating kinases, phosphoinositide-dependent kinase 1 ([[Phosphoinositide-dependent kinase-1|PDK1]]) and PDK2. Serine473, the hydrophobic motif, is phosphorylated in an mTORC2-dependent manner, leading some investigators to hypothesize that mTORC2 is the long-sought PDK2 molecule. Threonine308, the [[activation loop]], is phosphorylated by PDK1, allowing full Akt activation. Activated Akt can then go on to activate or deactivate its myriad substrates via its kinase activity. The PHLPPs therefore antagonize PDK1 and PDK2, since they dephosphorylate the site that PDK2 phosphorylates.<ref name="Brognard and Newton, 2008." />
== Dephosphorylation of protein kinase C ==
PHLPP1 and 2 also dephosphorylate the hydrophobic motifs of two classes of the [[protein kinase C]] (PKC) family: the conventional PKCs and the novel PKCs.  (The third class of PKCs, known as the atypicals, have a  [[phosphomimetics|phospho-mimetic]] at the hydrophobic motif, rendering them insensitive to PHLPP.)
The PKC family of kinases consists of 10 isoforms, whose sensitivity to various second messengers is dictated by their domain structure. The conventional PKCs can be activated by calcium and [[diacylglycerol]], two important mediators of [[G protein-coupled receptor]] signaling.  The novel PKCs are activated by diacylglycerol but not calcium, while the atypical PKCs are activated by neither.
The PKC family, like Akt, plays roles in cell survival and motility.  Most PKC isoforms are anti-apoptotic, although PKCδ (a novel PKC isoform) is pro-apoptotic in some systems.
Although PKC possesses the same phosphorylation sites as Akt, its regulation is quite different.  PKC is constitutively phosphorylated, and its acute activity is regulated by binding of the enzyme to membranes.  Dephosphorylation of PKC at the hydrophobic motif by PHLPP allows PKC to be dephosphorylated at two other sites (the activation loop and the turn motif).  This in turn renders PKC sensitive to degradation.  Thus, prolonged increases in PHLPP expression or activity inhibit PKC phosphorylation and stability, decreasing the total levels of PKC over time.<ref name="Brognard and Newton, 2008." />
== Role in cancer ==
Investigators have hypothesized that the PHLPP isoforms may play roles in cancer, for several reasons.  First, the genetic loci coding for PHLPP1 and 2 are commonly lost in cancer.  The region including PHLPP1, 18q21.33, commonly undergoes loss of heterozygosity ([[loss of heterozygosity|LOH]]) in colon cancers, while 16q22.3, which includes the PHLPP2 gene, undergoes LOH in breast and ovarian cancers, Wilms tumors, prostate cancer and hepatocellular carcinoma.<ref name="Brognard and Newton, 2008." />   Second, experimental overexpression of PHLPP in cancer cell lines tends to decrease apoptosis and increase proliferation, and stable colon and glioblastoma cell lines overexpressing PHLPP1 show decreased tumor formation in xenograft models.<ref name="Gao et al., 2005." /><ref name="pmid19079341">{{cite journal |vauthors=Liu J, Weiss HL, Rychahou P, Jackson LN, Evers BM, Gao T | title = Loss of PHLPP expression in colon cancer: Role in proliferation and tumorigenesis | journal = Oncogene | volume = 28 | issue = 7 | pages = 994–1004 |date=February 2009 | pmid = 19079341 | pmc = 2921630 | doi = 10.1038/onc.2008.450 }}</ref>  Recent studies have also shown that [[Bcr-abl fusion protein|Bcr-Abl]], the fusion protein responsible for chronic myelogenous leukemia ([[chronic myelogenous leukemia|CML]]), downregulates PHLPP1 and PHLPP2 levels, and that decreasing PHLPP levels interferes with the efficacy of Bcr-Abl inhibitors, including [[Gleevec]], in CML cell lines.<ref name="pmid19261608">{{cite journal |vauthors=Hirano I, Nakamura S, Yokota D, Ono T, Shigeno K, Fujisawa S, Shinjo K, Ohnishi K | title = Depletion of Pleckstrin Homology Domain Leucine-rich Repeat Protein Phosphatases 1 and 2 by Bcr-Abl Promotes Chronic Myelogenous Leukemia Cell Proliferation through Continuous Phosphorylation of Akt Isoforms | journal = J. Biol. Chem. | volume = 284| issue = 33| pages = 22155–65|date=March 2009 | pmid = 19261608 | doi = 10.1074/jbc.M808182200 | pmc = 2755940 | doi-access = free }}{{Retracted|doi=10.1074/jbc.A109.808182}}</ref>
Finally, both Akt and PKC are known to be tumor promoters, suggesting that their negative regulator PHLPP may act as a tumor suppressor.
==References==
{{Reflist}}
{{Esterases}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}
[[Category:EC 3.1.3]]
[[Category:Signal transduction]]