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• W2891551269 abstract "Review19 September 2018free access Protein palmitoylation and cancer Pin-Joe Ko Department of Biology, Stanford University, Stanford, CA, USA Search for more papers by this author Scott J Dixon Corresponding Author [email protected] orcid.org/0000-0001-6230-8199 Department of Biology, Stanford University, Stanford, CA, USA Search for more papers by this author Pin-Joe Ko Department of Biology, Stanford University, Stanford, CA, USA Search for more papers by this author Scott J Dixon Corresponding Author [email protected] orcid.org/0000-0001-6230-8199 Department of Biology, Stanford University, Stanford, CA, USA Search for more papers by this author Author Information Pin-Joe Ko1 and Scott J Dixon *,1 1Department of Biology, Stanford University, Stanford, CA, USA *Corresponding author. Tel: +1 650 725 1798; E-mail: [email protected] EMBO Rep (2018)19:e46666https://doi.org/10.15252/embr.201846666 See the Glossary for abbreviations used in this article. PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Protein S-palmitoylation is a reversible post-translational modification that alters the localization, stability, and function of hundreds of proteins in the cell. S-palmitoylation is essential for the function of both oncogenes (e.g., NRAS and EGFR) and tumor suppressors (e.g., SCRIB, melanocortin 1 receptor). In mammalian cells, the thioesterification of palmitate to internal cysteine residues is catalyzed by 23 Asp-His-His-Cys (DHHC)-family palmitoyl S-acyltransferases while the removal of palmitate is catalyzed by serine hydrolases, including acyl-protein thioesterases (APTs). These enzymes modulate the function of important oncogenes and tumor suppressors and often display altered expression patterns in cancer. Targeting S-palmitoylation or the enzymes responsible for palmitoylation dynamics may therefore represent a candidate therapeutic strategy for certain cancers. Glossary APT acyl-protein thioesterase ATM ataxia telangiectasia mutated ATR ataxia telangiectasia and Rad3 related cAMP cyclic adenosine monophosphate EGFR epidermal growth factor receptor Erf effect on ras function IP3R inositol 1,4,5-triphosphate receptor MC1R melanocortin 1 receptor PAT palmitoyl S-acyltransferase PTM post-translational modification ZDHHC zinc finger DHHC-type containing Introduction Hallmark cancer cell phenotypes such as sustained proliferation, resistance to cell death, and increased metastasis result from the altered activity of intracellular signaling, metabolic, and gene regulatory networks 1, 2. The function of these networks, both in normal and cancer cells, is regulated by dynamic post-translational modifications (PTMs) that alter protein localization, stability, and function. Hundreds of distinct PTMs impacting thousands of proteins have been identified in mammalian cells 3, 4. Protein lipidation—the post-translational addition of a lipid to a protein—comprises one important and diverse class of PTMs 5. Lipidated proteins generally have greater affinity for non-polar structures such as lipid bilayers, with important consequences for the localization, diffusion, and physical interactions of these proteins within the cell. Indeed, lipidation of key signaling proteins, such as Hedgehog, Wnt, and RAS, is essential for their function, both normally and in cancer 5-9. Many protein lipidation events are thought to be essentially irreversible, including N-myristoylation, S-farnesylation, O-palmitoylation, and N-palmitoylation. By contrast, protein S-palmitoylation (hereafter simply palmitoylation), which is the thioesterification of a sixteen-carbon saturated fatty acid (palmitate) to an internal cysteine residue, is a reversible modification. Indeed, proteins can cycle between palmitoylated and de-palmitoylated forms on timescales that range from seconds to hours 10-12. Dynamic palmitoylation can impact protein localization, accumulation, secretion, stability, and function by altering membrane affinity 5, 9, 13, 14. Understanding how protein palmitoylation influences the function of individual proteins in normal and cancer cells is an important driver of current research in this area. Currently, several hundred mammalian proteins, many of which are cancer-related, have been discovered to be palmitoylated 4, 15. While certain proteins are mono-palmitoylated, examples of proteins with as many as five or six individual palmitoylated cysteine residues are known 16. Some proteins spontaneously autopalmitoylate 17, 18. However, the majority of protein palmitoylation is catalyzed by the zinc finger DHHC-type containing (ZDHHC) family of palmitoyl S-acyltransferases (PATs), comprising 23 distinct proteins in mammals (Table 1) 19. Most ZDHHC proteins are localized to the ER and Golgi apparatus, the primary sites of protein palmitoylation activity within mammalian cells 10, 20, although at least three ZDHHC enzymes (ZDHHC5, ZDHHC20, ZDHHC21) appear primarily localized to the plasma membrane 21. Protein deacylation can be catalyzed by acyl-protein thioesterases (APTs) 1/2 (APT1/2, LYPLA1/2) belonging to the α/β-hydrolase family of serine hydrolases 22. Evidence links specific palmitoylated proteins and the function of individual PAT and APT enzymes to carcinogenesis and cancer cell growth, survival, and therapy resistance (Table 1, and see below). Thus, enzymes that modulate protein palmitoylation may be useful targets for anti-cancer treatments. The nature of protein palmitoylation, the enzymes involved, and the prospects for targeting these enzymes therapeutically are described below. Table 1. List of ZDHHC genes, alternative names, associated properties, and links to cancer Gene Alternative names UniProt ID Size (aa) Localization Cancer links ZDHHC1 Q8WTX9 485 ER High mRNA expression is a favorable prognostic marker in endometrial, renal, and pancreatic cancers (HPA) ZDHHC2 REAM Q9UIJ5 367 ER, Golgi In a fusion gene in acute myeloid leukemia; in a region of deletion in hepatocellular carcinoma; high expression is a favorable prognostic marker in gastric cancer; high mRNA expression is a favorable prognostic marker in renal cancer (HPA) ZDHHC3 GODZ Q9NYG2 327 Golgi High expression can be an unfavorable prognostic marker in breast carcinoma; in a region of recurrent loss in cervical cancer; high mRNA expression is a favorable prognostic marker in renal and colorectal cancer, but an unfavorable marker in liver cancer (HPA) ZDHHC4 Q9NPG8 344 Golgi High mRNA expression is a favorable prognostic marker in renal cancer, but an unfavorable marker in head and neck, urothelial, and cervical cancer (HPA) ZDHHC5 Q9C0B5 715 Plasma membrane High expression together with mutations in p53 are associated with reduced survival in glioma; high mRNA expression is an unfavorable prognostic marker in pancreatic cancer (HPA) ZDHHC6 Q9H6R6 413 ER – ZDHHC7 SERZ-beta Q9NXF8 308 Golgi In a region of deletion in breast carcinoma; deleted in prostate and ovarian cancer; high mRNA expression is an unfavorable prognostic marker in renal and liver cancer (HPA) ZDHHC8 Q9ULC8 765 Golgi High mRNA expression is an unfavorable prognostic marker in renal and cervical cancer (HPA) ZDHHC9 ZDHHC10, MMSA-1 Q9Y397 364 ER, Golgi Required for palmitoylation of RAS proteins and Nras-driven leukemias; high expression in a range of cancers including breast and colorectal cancer, and multiple myeloma; high mRNA expression is an unfavorable prognostic marker in cervical, breast, and head and neck cancers (HPA) ZDHHC11 Q9H8X9 412 ER High expression in Burkitt lymphoma cells promotes proliferation; frequently deleted in hepatoblastoma; in a region of amplification in non-small-cell lung carcinoma and bladder cancers; high mRNA expression of the non-coding ZDHHC11B transcript is a favorable prognostic marker in lung cancer (HPA) ZDHHC12 Q96GR4 267 ER, Golgi – ZDHHC13 HIP14L, HIP3RP Q8IUH4 622 ER, Golgi Required for protective function of MC1R against melanoma and to inhibit chemically induced papilloma ZDHHC14 Q8IZN3 488 ER Genomic deletions, mutations, and reduced expression in testicular germ cell tumor and prostate cancer; overexpression in scirrhous type gastric cancer and tongue squamous cell carcinoma; activating mutation (gene fusion) in acute biphenotypic leukemia; high mRNA expression is a favorable prognostic marker in pancreatic cancer (HPA) ZDHHC15 Q96MV8 337 Golgi – ZDHHC16 Aph2 Q969W1 377 ER – ZDHHC17 HIP14, HIP3, HYPH Q8IUH5 632 Golgi High mRNA expression is an unfavorable prognostic marker in renal cancer (HPA) ZDHHC18 Q9NUE0 388 Golgi High mRNA expression is an unfavorable prognostic marker in renal cancer, liver cancer, and glioma (HPA) ZDHHC19 Q8WVZ1 309 ER – ZDHHC20 Q5W0Z9 354 Plasma membrane Elevated mRNA expression in ovarian, breast, kidney, colon, and prostate cancer tissue; high mRNA expression is an unfavorable prognostic marker in renal and pancreatic cancer (HPA) ZDHHC21 Q8IVQ6 265 Plasma membrane High mRNA expression is a favorable prognostic marker in urothelial and renal cancer (HPA) ZDHHC22 Q8N966 263 ER, Golgi – ZDHHC23 NIDD Q8IYP9 409 ER High mRNA expression in B-precursor acute lymphoblastic leukemia; high mRNA expression is a favorable prognostic marker in renal cancer, but unfavorable in endometrial and thyroid cancer (HPA) ZDHHC24 Q6UX98 284 ER High mRNA expression is an unfavorable prognostic marker in glioblastoma (HPA) Localization data are from 21 and the UniProt database. Cancer links is defined broadly as any literature link between a ZDHHC-family member and a particular cancer, including large-scale and small-scale experimental studies, animal and cell culture studies, and clinical studies, whether functional or correlative. References: ZDHHC2 70, 129, 130, ZDHHC3 131-133, ZDHHC5 87, ZDHHC7 47, 134, ZDHHC9 89, 92, 135, 136, ZDHHC11 77, 78, 137, 138, ZDHHC13 49, 73, ZDHHC14 82-85, ZDHHC20 81, ZDHHC23 139. HPA, Human Protein Atlas (www.proteinatlas.org/). Protein S-palmitoylation: basic biochemical mechanisms Studies of the Saccharomyces cerevisiae integral membrane proteins Erf2 (effect on ras function 2) and Akr1 (ankyrin-repeat containing 1) were the first to firmly establish the enzymatic basis of protein palmitoylation and provided the first insights into the structure and function of enzymes catalyzing this reaction 23-25 (Fig 1A). The recent crystal structure of human ZDHHC20 confirmed and extended these earlier biochemical studies 26. ZDHHC20 adopts a teepee-like structure (wide at the cytoplasmic side, narrow at the membrane-internal side) with the Asp-His-His-Cys (DHHC) enzyme active site located on the cytosolic linker between transmembrane domains 2 and 3. Here, it is positioned to interact with both palmitoyl-CoA and substrate proteins at the membrane–cytosol interface. Palmitoyl-CoA first reacts with the cysteine residue in the DHHC motif itself, forming an acyl-intermediate and releasing free CoA-SH (i.e., autopalmitoylation). This intermediate is then transferred from the DHHC motif directly to substrate proteins in the cell. Cysteine residues that lie near the catalytic DHHC motif coordinate two structural zinc atoms that are essential for proper enzyme folding and function, but do not play a catalytic role in palmitate transfer 26-28. Despite overall amino acid similarity, the 23 human ZDHHC enzymes exhibit distinct abilities to autoacylate, implying differences in catalytic efficiency 29, 30. Of note, while often referred to in general as “palmitoylation”, this process can involve not only the addition of palmitate (C16:0), but also other fatty acids with different chain lengths (e.g., C18:0, stearoylation) 31. Indeed, mammalian ZDHHC enzymes display distinct fatty acyl preferences 32, 33, with the ability to preferentially accommodate particular fatty acyl chain lengths specified by amino acids that cap the hydrophobic cavity of the protein 26. Figure 1. The biochemistry of protein palmitoylation(A) Palmitate (derived from palmitoyl-CoA) can be thioesterified to substrate proteins by DHHC (Asp-His-His-Cys)-family protein S-acyltransferases (PATs). DHHC PATs are integral membrane proteins (blue) with the active site oriented toward the cytosol. These enzymes catalyze palmitoylation on internal cysteine (Cys) residues of substrate proteins (S-acylation). The DHHC enzyme is first autopalmitoylated on the DHHC cysteine residue with the release of free coenzyme A (CoA), followed by a transfer of the palmitate group to the acceptor cysteine residue of a substrate protein (purple). (B) Acylprotein thioesterase (APT, green) can remove palmitate groups from palmitoylated proteins (purple). APT1/2 are themselves palmitoylated and contain a hydrophobic pocket to accept palmitoylated substrates and position the substrate palmitoylated cysteine near the active site serine (Ser) residue. Download figure Download PowerPoint How ZDHHC enzymes select substrate proteins for modification is not entirely clear as there is no consensus palmitoylation sequence. Palmitoylated proteins are often substrates for more than one ZDHHC enzyme, but one particular ZDHHC enzyme often has a stronger effect than others on substrate palmitoylation in the cell (e.g. 29, 34-36). Chimeric ZDHHC proteins and structure–function studies have defined specific regions of individual ZDHHC enzymes that promote substrate interaction and palmitoylation, indicating that unique substrate-binding preferences could guide the palmitoylation of certain proteins 5. For other proteins, palmitoylation requires an initial lipidation event (e.g., RAS C-terminal farnesylation, SRC-family N-terminal myristoylation) at an amino acid residue near the to-be palmitoylated Cys residue(s), which likely helps localize the substrate to ZDHHC-enriched membranes (e.g., the Golgi) 37-39. Two ZDHHC enzymes, ZDHHC13 and ZDHHC17, contain unique C-terminal ankyrin-repeat domains that can bind certain proteins and enhance their membrane localization, facilitating palmitoylation by other ZDHHC enzymes 30, 40. Efficient palmitoylation by some DHHC enzymes (Erf2/ZDHHC9, ZDHHC6) requires an accessory protein (Erf4/GOLGA7, SELENOK), and speculatively, these accessory proteins could aid in substrate selection 24, 41-44. S-palmitoylation occurs on internal cysteine residues of substrate proteins, and within a given protein, only specific cysteine residues are S-palmitoylated. Despite progress in computational prediction 45, 46, it remains difficult to determine a priori which specific cysteines within a given protein will be modified, and experimental trial-and-error remains essential to define palmitoylated residues (e.g. 47-49). Due to the location and orientation of the DHHC motif, palmitoylation of integral membrane proteins occurs preferentially on cysteines located within eight angstroms of the membrane–cytosol interface, providing a structural constraint on the palmitoylation potential of certain residues 26, 50. For peripheral membrane proteins, the ZDHHC-substrate binding conformation appears to be important for effective palmitoylation to occur on specific residues; substrate mutations distal to the sites of palmitoylation can strongly impact the likelihood of modification 47, 49. How substrate conformation or binding influences palmitoylation remains to be worked out in detail. The enzymatic removal of S-acyl modifications in mammalian cells is catalyzed by a family of serine hydrolases 51 (Fig 1B). The first enzyme, APT1, was reported to depalmitoylate the alpha subunit of G proteins and HRAS in vitro 52. However, it appears that in cells APT2 is a cytosolic enzyme while APT1 is localized to the mitochondria, which may explain the selective effect of APT2 inhibition on the palmitoylation of cytosolic proteins 53, 54. APT1 and APT2 are not the only thioesterases in the cell and in fact do not impact the palmitoylation of key cancer-related proteins in the cell 11, 54; ABHD17A, ABHD17B, and ABHD17C are novel depalmitoylation enzymes that regulate the palmitoylation status of NRAS, for example 51, 55, 56. Finally, palmitoyl protein thioesterases 1 and 2 (PPT1/2) localize to and deacylate proteins in the lysosome. PAT and APT enzymes can exist within complex regulatory networks. ZDHHC5, ZDHHC6, and ZDHHC8 are palmitoylated at cysteine residues outside the catalytic DHHC motif 57, and these modifications are likely essential for normal enzyme localization and function. Recently, ZDHHC16 was shown to physically associate with and palmitoylate ZDHHC6 on Cys328, Cys329, and Cys343 residues found within the ZDHHC6 C-terminal Src homology 3 (SH3) domain 36 (Fig 2A). Modeling and experimental studies suggest that this palmitoylation “cascade”, from ZDHHC16 to ZDHHC6, enhances the overall stability and activity of ZDHHC6, although different configurations of modifications yield distinct activity and stability profiles. Palmitoylation of ZDHHC6 at these C-terminal cysteine residues is reversible by APT2, with turnover on Cys328 being especially rapid (Fig 2B). Adding further complexity to this network, APT1/2 and ABDH-family thioesterases are also themselves palmitoylated, and this modification is necessary for their proper localization and function 57, 58. For example, ABHD17A-C proteins have a highly conserved cluster of cysteines near the N-terminus that are required for proper localization to plasma and endosomal membranes and optimal catalytic activity 51. PPT1 is also palmitoylated by ZDHHC3 and ZDHHC7, but in this case, palmitoylation decreases enzyme activity 59. The function of both PAT (e.g., ZDHHC13, ZDHHC3) and APT (e.g., APT1) enzymes can also be regulated by phosphorylation in cancer and other cells, downstream of different signaling pathways 49, 60, 61. Thus, a web of interconnected PTMs regulates both ZDHHC and thioesterase localization and activity, with important implications for the regulation of cancer-associated substrates. Figure 2. A highly connected web of palmitoylation events(A) ER-resident ZDHHC6 can autopalmitoylate, like other DHHC family members. In addition, three cysteine residues within the C-terminal tail of ZDHHC6 are palmitoylated by a distinct enzyme, ZDHHC16, representing a palmitoylation cascade. (B) The acylprotein thioesterase APT2, which itself requires palmitoylation to function normally, can remove the C-terminal palmitoyl groups on ZDHHC6. Download figure Download PowerPoint Protein palmitoylation and cancer: connecting the dots Several important cancer-associated proteins are palmitoylated. A classic example is provided by the RAS family of small GTPases 62, 63. In addition to being irreversibly farnesylated at a conserved C-terminal CaaX sequence, HRAS, NRAS, and the KRAS-4A isoform (but not the KRAS-4B isoform) are reversibly S-palmitoylated at one (NRAS, KRAS-4A) or two (HRAS) internal cysteine residues. RAS that is both farnesylated and palmitoylated has a 100-fold greater affinity for membranes than RAS that is only farnesylated 64. Only the dually lipidated (i.e., farnesylated and palmitoylated) forms of HRAS, NRAS, and KRAS-4A are properly localized to the plasma membrane and capable of transforming cells, with the distinct patterns of lipid modification found between these closely related GTPases dictating trafficking and signaling properties 55, 65-68. Looking more broadly, intersecting a recent list of 299 validated cancer driver genes 69 with the results of fifteen palmitoylome studies currently available in SwissPalm suggests that 78 (26%) of the encoded proteins may be palmitoylated, highlighting the relevance of this modification to cancer (Fig 3). For most cancer-relevant palmitoylated proteins, the responsible ZDHHC enzyme(s) is not known. Figure 3. Many cancer drivers are palmitoylatedBailey et al 69 identified a set of 299 cancer drivers, 78 of which are annotated in SwissPalm (Dataset 3) as being palmitoylated in at least one of fifteen proteomics studies. A subset of the most frequently identified proteins are shown in the box, indicating how many times they have been discovered as palmitoylated in high-throughput studies (15 total). Download figure Download PowerPoint The role of protein palmitoylation in cancer can also be approached from the direction of the PAT and APT enzymes, many of which display associations with cancer. Here, we focus on ZDHHC enzymes that are linked to cancer as candidate oncoproteins, tumor suppressors, or prognostic markers (Table 1). For example, low ZDHHC2 expression is found in gastric adenocarcinoma and associated with lymph node metastasis 70, and low Zdhhc2 expression is found in highly metastatic murine colorectal adenocarcinoma clones 71, 72. Truncation mutations in Zdhhc13 (Hip14l) increase susceptibility to chemically induced skin cancer in mice, possibly through enhanced NF-κB signaling 73. Thus, ZDHHC2 and ZDHHC13 could act as tumor suppressors, but links between these enzymes, candidate substrates 74-76, and tumor suppression are unclear. A similar situation exists in relation to ZDHHC enzymes that may act as oncoproteins. ZDHHC11 is found on chromosome 5 in a small region of recurrent amplification in non-small-cell lung and high-grade bladder cancers 77, 78. ZDHHC17 (also known as HIP14) is upregulated in several tumor types, including breast and colon, and overexpression of this enzyme can also transform NIH 3T3 cells 79, 80. Overexpression of ZDHHC20 can likewise transform NIH 3T3 cells 81. The specific substrate protein(s) that link increased ZDHHC11, ZDHHC17, or ZDHHC20 expression to cancer are not known. In some cases, there are conflicting associations between ZDHHC expression and cancer. Many testicular germ cell tumors contain genomic deletions, mutations, or other alterations that reduce ZDHHC14 expression, suggesting that this enzyme could act as a tumor suppressor in this disease 82. Indeed, overexpression of ZDHHC14 can slow xenograft tumor formation and induce apoptosis in cultured HEK 293 cells 82. However, studies of scirrhous type gastric cancer, tongue squamous cell carcinoma, and a patient with acute biphenotypic leukemia indicate that expression and/or activation of ZDHHC14 could be oncogenic in these diseases through enhanced cell migration or reduced terminal differentiation 83-85. In other cases, functional studies have disclosed a role for a particular ZDHHC enzyme in cancer development without any obvious change in gene or protein expression level. In lung cancer, ZDHHC5 expression levels are not associated with overall survival, but short interfering RNA (siRNA)-mediated silencing of ZDHHC5 leads to reduced cell proliferation, colony formation, cell migration, and xenograft tumor growth 86. By contrast, in glioma cells, high ZDHHC5 expression is predictive of poorer prognosis, and this overexpression appears to be driven by oncogenic mutations in the tumor suppressor protein p53 87. These results suggest that individual ZDHHC enzymes can act as either oncoproteins or tumor suppressors in a tissue-specific and/or cancer type-specific manner. These opposing roles may be explained by differences in the relative expression of ZDHHC enzymes and one or more key substrates between tissues. The effect of deleting or overexpressing a single ZDHHC gene on cancer phenotypes could also be masked in a given tissue due to functional redundancy. Because of this complexity, how the expression of individual ZDHHC enzymes alters substrate palmitoylation to influence cancer phenotypes is often difficult to establish. To most clearly illustrate the different ways in which protein palmitoylation can impact cancer, we describe below in greater detail several recent examples where enzyme–substrate–phenotype “triads” have been more firmly established. Regulation of oncogenic RAS signaling from the plasma membrane Palmitoylation of HRAS, NRAS, and KRAS-4A at the Golgi ensures the proper delivery of these proteins to the plasma membrane via the secretory system 62. In vivo, NRAS-driven leukemogenesis is palmitoylation-dependent: mice transplanted with bone marrow cells expressing oncogenic human NRASG12D die of leukemia-like diseases within 3 months, while those transplanted with cells expressing an activated but non-palmitoylatable mutant (NRASG12D,C181S) remain healthy for up to 2 years 88. Mechanistically, inhibition of palmitoylation does not impair GTP loading of NRAS but rather prevents its normal plasma membrane localization and the hyperactivation of downstream signaling effectors such as Akt, Erk1/2, and Ral 88. This clearly demonstrates that oncogenic NRAS signaling requires palmitoylation-dependent plasma membrane localization. Similarly to S. cerevisiae Ras2, which is palmitoylated by the Erf2-Erf4 PAT complex, mammalian NRAS and HRAS are palmitoylated by an orthologous Golgi-localized complex comprising ZDHHC9 and GOLGA7 42, 89 (Fig 4A). Interestingly, mammalian GOLGA7 is itself palmitoylated by an unknown ZDHHC enzyme and this modification is essential for its stability and localization to the Golgi apparatus, as well as for ZDHHC9 function 42, 90. Indeed, GOLGA7 has been identified as a selective dependency in NRAS-mutant human AML cell lines, highlighting the importance of accessory subunits in ZDHHC function 91. In mice lacking Zdhhc9, NrasG12D-driven T-cell acute lymphocytic leukemia and chronic myelomonocytic leukemia are both significantly attenuated but not completely prevented 92. The incomplete phenotypic suppression implies that additional PATs likely palmitoylate Nras in vivo 92. Figure 4. Examples of protein palmitoylation and cancer(A) The NRAS GTPase has a conserved C-terminal CaaX motif that is farnesylated and O-methylated (OMe), then palmitoylated by the Golgi-resident ZDHHC9-GOLGA7 complex. Dually lipidated NRAS is properly anchored in the plasma membrane. (B) SCRIB is localized to the plasma membrane by ZDHHC7-catalyzed palmitoylation. SCRIB regulates the Hippo kinase cascade, ultimately phosphorylating YAP and TAZ, occluding them from the nucleus. (C) In response to ultraviolet (UV) radiation-induced DNA damage, ATR phosphorylates ZDHHC13, activating it. ZDHHC13 palmitoylates MC1R, which can then drive cAMP-dependent MITF transcriptional activation of melanin synthesis and DNA repair to mitigate DNA damage. Certain MC1R alleles, termed RHC variants, are found in cancer-sensitive populations and have mutations that reduce MC1R palmitoylation. This results in downregulation of the DNA damage response and sensitization of the cells to damage. (D) Inositol-1,4,5-triphosphate (IP3) activates the receptor IP3R, a tetrameric Ca2+ channel, to stimulate calcium release. IP3R monomers are palmitoylated by a ZDHHC6-SELENOK complex, with the selenocysteine (Sec) residue of SELENOK being essential to stabilize the autoacylated ZDHHC6 intermediate. Download figure Download PowerPoint Regulation of tumor suppressor localization to the plasma membrane Another example of palmitoylation-dependent control over protein localization is provided by Scribble (SCRIB). SCRIB is a tumor suppressor critical for regulating epithelial cell polarity 93, 94. Loss of SCRIB inactivates the Hippo kinase cascade, leading to the accumulation of unphosphorylated Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in the nucleus, and increased mitogen-activated protein kinase (MAPK) and AKT pathway activity 47, 54, 95, 96. To activate the Hippo kinase cascade and repress MAPK and AKT signaling, SCRIB must be localized to the plasma membrane. This localization is dependent upon palmitoylation of Cys4 and Cys10 in the N-terminus of SCRIB, most likely by ZDHHC7, but with other enzymes potentially contributing to this process 47, 54 (Fig 4B). Overexpression of the transcription factor SNAIL promotes intracellular mislocalization of SCRIB, likely through the coordinate downregulation of multiple ZDHHC enzymes and upregulation of APT2, leading to loss of protein palmitoylation 54. Treatment with the specific APT2 inhibitor ML349 results in stabilization of SCRIB at the plasma membrane by enhancing the palmitoylation of this protein 54. While the effects of this treatment on SCRIB-dependent tumor cell growth in vivo have not been examined, the expectation is that increased membrane retention would result in decreased tumorigenicity. Regulation of G protein-coupled receptor activity In melanocytes, ZDHHC13-dependent palmitoylation of the plasma membrane α-melanocyte-stimulating hormone (α-MSH) receptor, melanocortin-1 receptor (MC1R), at Cys315 is required for MC1R tumor suppressor function 49. Specifically, only properly palmitoylated MC1R can stimulate sufficient cyclic adenosine monophosphate (cAMP) production to induce a protective transcriptional cascade in response to UV irradiation and consequent DNA damage. Cancer-sensitizing mutations (e.g., R151C and R160W, found in people with red hair or fair skin, termed red hair color (RHC) variants) reduce Cys315 palmitoylation and attenuate cAMP production (Fig 4C). Whether this attenuation of signaling is due to mislocalization of the RHC-variant MC1R or due to loss of MC1R activity remains unclear. Regardless, this signaling defect can be rescued by overexpression of ZDHHC13 or treatment with the thioesterase inhibitor palmostatin B, which restores MC1R-RHC palmitoylation and attenuates the tumorigenic effects of UV irradiation in a" @default.
• W2891551269 created "2018-09-27" @default.
• W2891551269 creator A5047039050 @default.
• W2891551269 creator A5064348534 @default.
• W2891551269 date "2018-09-19" @default.
• W2891551269 modified "2023-10-11" @default.
• W2891551269 title "Protein palmitoylation and cancer" @default.
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