PHLPP

Last updated
PH domain and leucine-rich repeat protein phosphatase
Identifiers
Symbol PHLPP
Alt. symbolsPHLPP1, PLEKHE1
NCBI gene 23239
HGNC 20610
OMIM 609396
RefSeq XM_166290
UniProt O60346
Other data
EC number 3.1.3.16
Locus Chr. 18 q21.32
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Structures Swiss-model
Domains InterPro
PH domain and leucine rich repeat protein phosphatase-like
Identifiers
Symbol PHLPPL
Alt. symbolsPHLPP2
NCBI gene 23035
HGNC 29149
OMIM 611066
RefSeq NM_015020
UniProt Q6ZVD8
Other data
EC number 3.1.3.16
Locus Chr. 16 q22.2
Search for
Structures Swiss-model
Domains InterPro

The PHLPP isoforms (PH domain and Leucine rich repeat Protein Phosphatases) are a pair of protein phosphatases, PHLPP1 and PHLPP2, that are important regulators of Akt serine-threonine kinases (Akt1, Akt2, 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. [1]

Contents

PHLPP dephosphorylates Ser-473 (the hydrophobic motif) in Akt, thus partially inactivating the kinase. [2]

In addition, PHLPP dephosphorylates conventional and novel members of the protein kinase C family at their hydrophobic motifs, corresponding to Ser-660 in PKCβII. [3]

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 association domain, a pleckstrin homology domain, a series of leucine-rich repeats, a PP2C phosphatase domain, and a C-terminal 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-terminal portion of the protein, including the Ras association domain. [1] 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. [2]

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. [4]

The Akt family of kinases

In humans, there are three genes in the Akt family: AKT1, AKT2, and AKT3. These enzymes are members of the serine/threonine-specific protein kinase family (EC 2.7.11.1).

Akt1 is involved in cellular survival pathways and inhibition of 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 ]

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 diabetic phenotype (insulin resistance), again consistent with the idea that Akt2 is more specific for the insulin receptor signaling pathway. [5]

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. [6]

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 (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. [1]

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 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. [1]

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 (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. [1] 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. [2] [7] Recent studies have also shown that Bcr-Abl, the fusion protein responsible for 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. [8]

Finally, both Akt and PKC are known to be tumor promoters, suggesting that their negative regulator PHLPP may act as a tumor suppressor.

Related Research Articles

In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins, or a member of this family. PKC enzymes in turn are activated by signals such as increases in the concentration of diacylglycerol (DAG) or calcium ions (Ca2+). Hence PKC enzymes play important roles in several signal transduction cascades.

<span class="mw-page-title-main">Protein kinase B</span> Set of three serine threonine-specific protein kinases

Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration.

<i>PTEN</i> (gene) Tumor suppressor gene

Phosphatase and tensin homolog (PTEN) is a phosphatase in humans and is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers, specifically glioblastoma, lung cancer, breast cancer, and prostate cancer. Genes corresponding to PTEN (orthologs) have been identified in most mammals for which complete genome data are available.

<span class="mw-page-title-main">Phosphoinositide 3-kinase</span> Class of enzymes

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 in turn are involved in cancer.

<span class="mw-page-title-main">Receptor tyrosine kinase</span> Class of enzymes

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. The receptors are generally activated by dimerization and substrate presentation. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.

<span class="mw-page-title-main">Platelet-derived growth factor receptor</span> Cell surface receptors

Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including cancer. There are two forms of the PDGF-R, alpha and beta each encoded by a different gene. Depending on which growth factor is bound, PDGF-R homo- or heterodimerizes.

The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor (EGFR), its first discovered member. In humans, the family includes Her1, Her2 (ErbB2), Her3 (ErbB3), and Her4 (ErbB4). The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: erythroblastic leukemia viral oncogene. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's disease, while excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor.

<span class="mw-page-title-main">AKT1</span> Protein-coding gene in the species Homo sapiens

RAC(Rho family)-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene. This enzyme belongs to the AKT subfamily of serine/threonine kinases that contain SH2 protein domains. It is commonly referred to as PKB, or by both names as "Akt/PKB".

<span class="mw-page-title-main">PRKCD</span> Protein-coding gene in the species Homo sapiens

Protein kinase C delta type is an enzyme that in humans is encoded by the PRKCD gene.

<span class="mw-page-title-main">AKT2</span> Protein-coding gene in the species Homo sapiens

AKT2, also known as RAC-beta serine/threonine-protein kinase, is an enzyme that in humans is encoded by the AKT2 gene. It influences metabolite storage as part of the insulin signal transduction pathway.

<span class="mw-page-title-main">AKT3</span> Protein-coding gene in the species Homo sapiens

RAC-gamma serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT3 gene.

<span class="mw-page-title-main">PDK2</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase kinase isoform 2 (PDK2) also known as pyruvate dehydrogenase lipoamide kinase isozyme 2, mitochondrial is an enzyme that in humans is encoded by the PDK2 gene. PDK2 is an isozyme of pyruvate dehydrogenase kinase.

<span class="mw-page-title-main">PKN2</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase N2 is an enzyme that in humans and Strongylocentrotus purpuratus is encoded by the PKN2 gene.

<span class="mw-page-title-main">RPTOR</span> Protein-coding gene in humans

Regulatory-associated protein of mTOR also known as raptor or KIAA1303 is an adapter protein that is encoded in humans by the RPTOR gene. Two mRNAs from the gene have been identified that encode proteins of 1335 and 1177 amino acids long.

<span class="mw-page-title-main">Protein phosphorylation</span> Process of introducing a phosphate group on to a protein

Protein phosphorylation is a reversible post-translational modification of proteins in which an amino acid residue is phosphorylated by a protein kinase by the addition of a covalently bound phosphate group. Phosphorylation alters the structural conformation of a protein, causing it to become activated, deactivated, or otherwise modifying its function. Approximately 13,000 human proteins have sites that are phosphorylated.

The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K and Akt.

<span class="mw-page-title-main">Phosphoinositide-dependent kinase-1</span> Protein-coding gene in the species Homo sapiens

In the field of biochemistry, PDPK1 refers to the protein 3-phosphoinositide-dependent protein kinase-1, an enzyme which is encoded by the PDPK1 gene in humans. It is implicated in the development and progression of melanomas.

Epstein–Barr virus (EBV) latent membrane protein 2 (LMP2) are two viral proteins of the Epstein–Barr virus. LMP2A/LMP2B are transmembrane proteins that act to block tyrosine kinase signaling. LMP2A is a transmembrane protein that inhibits normal B-cell signal transduction by mimicking an activated B-cell receptor (BCR). The N-terminus domain of LMP2A is tyrosine phosphorylated and associates with Src family protein tyrosine kinases (PTKs) as well as spleen tyrosine kinase (Syk). PTKs and Syk are associated with BCR signal transduction.

<span class="mw-page-title-main">PI3K/AKT/mTOR pathway</span> Cell cycle regulation pathway

The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. Therefore, it is directly related to cellular quiescence, proliferation, cancer, and longevity. PI3K activation phosphorylates and activates AKT, localizing it in the plasma membrane. AKT can have a number of downstream effects such as activating CREB, inhibiting p27, localizing FOXO in the cytoplasm, activating PtdIns-3ps, and activating mTOR which can affect transcription of p70 or 4EBP1. There are many known factors that enhance the PI3K/AKT pathway including EGF, shh, IGF-1, insulin, and CaM. Both leptin and insulin recruit PI3K signalling for metabolic regulation. The pathway is antagonized by various factors including PTEN, GSK3B, and HB9.

<span class="mw-page-title-main">Alexandra Newton</span> US-based Protein Kinase C expert

Alexandra C. Newton is a Canadian and American biochemist. She is a Distinguished Professor of pharmacology at the University of California, San Diego. Newton runs a multidisciplinary Protein kinase C and Cell signaling biochemistry and cell biology research group in the School of Medicine, investigating molecular mechanisms of signal transduction in the Phospholipase C (PLC) and Phosphoinositide 3-kinase signaling pathways. She has been continuously funded by the US National Institutes of Health since 1988.

References

  1. 1 2 3 4 5 Brognard J, Newton AC (August 2008). "PHLiPPing the Switch on Akt and Protein Kinase C Signaling". Trends Endocrinol. Metab. 19 (6): 223–30. doi:10.1016/j.tem.2008.04.001. PMC   2963565 . PMID   18511290.
  2. 1 2 3 Gao T, Furnari F, Newton AC (April 2005). "PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth". Mol. Cell. 18 (1): 13–24. doi: 10.1016/j.molcel.2005.03.008 . PMID   15808505.
  3. ↑ Gao T, Brognard J, Newton AC (March 2008). "The phosphatase PHLPP controls the cellular levels of protein kinase C". J. Biol. Chem. 283 (10): 6300–11. doi: 10.1074/jbc.M707319200 . PMID   18162466.
  4. ↑ Brognard J, Sierecki E, Gao T, Newton AC (March 2007). "PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms". Mol. Cell. 25 (6): 917–31. doi: 10.1016/j.molcel.2007.02.017 . PMID   17386267.
  5. ↑ Garofalo RS, Orena SJ, Rafidi K, Torchia AJ, Stock JL, Hildebrandt AL, Coskran T, Black SC, Brees DJ, Wicks JR, McNeish JD, Coleman KG (July 2003). "Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKBβ". J. Clin. Invest. 112 (2): 197–208. doi:10.1172/JCI16885. PMC   164287 . PMID   12843127.
  6. ↑ Dummler B, Tschopp O, Hynx D, Yang ZZ, Dirnhofer S, Hemmings BA (November 2006). "Life with a Single Isoform of Akt: Mice Lacking Akt2 and Akt3 Are Viable but Display Impaired Glucose Homeostasis and Growth Deficiencies". Mol. Cell. Biol. 26 (21): 8042–51. doi:10.1128/MCB.00722-06. PMC   1636753 . PMID   16923958.
  7. ↑ Liu J, Weiss HL, Rychahou P, Jackson LN, Evers BM, Gao T (February 2009). "Loss of PHLPP expression in colon cancer: Role in proliferation and tumorigenesis". Oncogene. 28 (7): 994–1004. doi:10.1038/onc.2008.450. PMC   2921630 . PMID   19079341.
  8. ↑ Hirano I, Nakamura S, Yokota D, Ono T, Shigeno K, Fujisawa S, Shinjo K, Ohnishi K (March 2009). "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". J. Biol. Chem. 284 (33): 22155–65. doi: 10.1074/jbc.M808182200 . PMC   2755940 . PMID   19261608. (Retracted, see doi:10.1074/jbc.A109.808182 . If this is an intentional citation to a retracted paper, please replace {{ retracted |...}} with {{ retracted |...|intentional=yes}}.)
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