Ser419

Site Information
GGRsRsGsIVELIAG SwissProt Entrez-Gene
Blast this site against: NCBI SwissProt PDB
Site Group ID: 448106
Associated spectra: 1 CST

In vivo Characterization
Methods used to characterize site in vivo:	immunoassay ( 1 ) , immunoprecipitation ( 14 ) , mass spectrometry ( 2 , 3 , 6 , 7 , 9 , 10 , 11 , 12 , 14 , 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 40 , 41 , 42 , 43 , 44 , 46 , 47 , 48 , 49 ) , mutation of modification site ( 1 , 5 , 8 , 14 , 39 , 45 , 50 , 51 , 52 , 53 ) , phospho-antibody ( 2 , 4 , 8 , 13 , 45 , 50 , 51 , 52 , 53 ) , western blotting ( 2 , 4 , 5 , 8 , 13 , 14 , 39 , 45 , 50 , 52 , 53 )
Disease tissue studied:	breast cancer ( 7 , 11 , 12 ) , HER2 positive breast cancer ( 6 ) , luminal A breast cancer ( 6 ) , luminal B breast cancer ( 6 ) , breast cancer, surrounding tissue ( 6 ) , breast cancer, triple negative ( 6 , 11 ) , gastric cancer ( 24 ) , gastric carcinoma ( 24 ) , leukemia ( 1 , 18 , 25 , 26 , 27 , 28 , 29 ) , acute myelogenous leukemia ( 18 ) , chronic myelogenous leukemia ( 1 , 25 , 26 , 27 , 28 , 29 ) , hepatocellular carcinoma, surrounding tissue ( 32 ) , lung cancer ( 17 , 33 ) , non-small cell lung cancer ( 17 ) , non-small cell lung adenocarcinoma ( 33 ) , non-small cell squamous cell lung carcinoma ( 33 ) , neuroblastoma ( 4 , 45 , 50 ) , pancreatic ductal adenocarcinoma ( 15 ) , Huntington's disease ( 8 )
Relevant cell line - cell type - tissue:	'brain, striatum' ( 13 , 50 ) , 'neuron, cortical'-brain ( 39 , 51 , 52 ) , 'pancreatic, ductal'-pancreas ( 15 ) , 'stem, induced pluripotent' ( 1 ) , 293 (epithelial) [AT1 (human), transfection, AT1R stable transfected HEK293] ( 30 ) , 293 (epithelial) ( 1 , 9 , 19 , 20 , 21 , 22 , 35 , 39 , 51 ) , 293E (epithelial) ( 23 ) , 293FT ( 14 ) , breast ( 6 , 11 ) , Calu 6 (pulmonary) ( 17 ) , EBV-LCL (lymphoblast) ( 8 ) , fibroblast ( 5 ) , H2009 (pulmonary) ( 17 ) , H2077 (pulmonary) ( 17 ) , H2887 (pulmonary) ( 17 ) , H322M (pulmonary) ( 17 ) , HCC1359 (pulmonary) ( 17 ) , HCC2279 (pulmonary) ( 17 ) , HCC366 (pulmonary) ( 17 ) , HCC4006 (pulmonary) ( 17 ) , HCC78 (pulmonary) ( 17 ) , HCC827 (pulmonary) ( 17 ) , HEK293T (epithelial) ( 13 , 49 , 52 , 53 ) , HeLa (cervical) ( 10 , 34 , 48 , 51 ) , hepatocyte-liver ( 32 ) , HMLER ('stem, breast cancer') [CXCR4 (human), knockdown] ( 12 ) , HMLER ('stem, breast cancer') ( 12 ) , HOP62 (pulmonary) ( 17 ) , Jurkat (T lymphocyte) ( 31 , 50 ) , K562 (erythroid) ( 1 , 25 , 26 , 27 , 28 , 29 , 47 ) , KG-1 (myeloid) ( 18 ) , LCL (lymphoblastoid) ( 2 ) , LCLC-103H (pulmonary) ( 17 ) , LOU-NH91 (squamous) ( 17 ) , MCF-7 (breast cell) ( 7 ) , MKN-45 (gastric) ( 24 ) , NCI-H1395 (pulmonary) ( 17 ) , NCI-H1568 (pulmonary) ( 17 ) , NCI-H157 (pulmonary) ( 17 ) , NCI-H1648 (pulmonary) ( 17 ) , NCI-H1666 (pulmonary) ( 17 ) , NCI-H1703 (squamous) ( 33 , 36 , 37 , 38 , 42 , 43 , 44 ) , NCI-H2030 (pulmonary) ( 17 ) , NCI-H2172 (pulmonary) ( 17 ) , NCI-H322 (pulmonary) ( 17 ) , NCI-H3255 (pulmonary) ( 33 , 40 , 41 ) , NCI-H460 (pulmonary) ( 17 ) , NCI-H520 (squamous) ( 17 ) , NCI-H647 (pulmonary) ( 17 ) , neuron ( 4 , 45 ) , neuron-'brain, cerebral cortex' ( 14 , 45 ) , PC-12 (chromaffin) ( 49 ) , PC9 (pulmonary) ( 17 ) , platelet-blood ( 46 ) , SF9 ( 2 ) , SH-SY5Y (neural crest) ( 4 , 45 , 50 ) , STHdh ('neuron, striatal') ( 13 ) , Vero E6-S ('epithelial, kidney') ( 3 )

Upstream Regulation
Regulatory protein:	5-HT(2C) (human) ( 13 ) , ADRA2A (human) ( 13 ) , ADRB2 (human) ( 13 ) , Akt1 (human) ( 50 ) , ARRB2 (human) ( 13 ) , CNR1 (human) ( 13 ) , DRD1 (human) ( 13 ) , DRD2 (human) ( 13 ) , DRD4 (human) ( 13 ) , DRD5 (human) ( 13 ) , PPP3CA (human) ( 50 )
Putative in vivo kinases:	Akt1 (human) ( 52 , 53 ) , SGK1 (human) ( 52 )
Kinases, in vitro:	Akt1 (human) ( 50 , 51 , 53 ) , SGK1 (human) ( 52 )
Putative upstream phosphatases:	PPM1B (human) ( 13 ) , PPP3CA (human) ( 50 ) , PPPM1A (human) ( 13 )
Phosphatases, in vitro:	PPM1B (human) ( 13 ) , PPP2CA (human) ( 51 ) , PPP3CA (human) ( 50 ) , PPPM1A (human) ( 13 )
Treatments:	127153 ( 13 ) , 5-HT ( 13 ) , 6-OHDA ( 4 ) , apomorphine ( 13 ) , bromocriptine ( 13 ) , cadmium_chloride ( 13 ) , ciclosporin ( 13 ) , cypermethrin ( 13 ) , EGF ( 34 ) , exenatide ( 4 ) , FK506 ( 50 ) , haloperidol ( 13 ) , IGF-1 ( 8 , 39 , 53 ) , insulin ( 4 , 8 ) , ionomycin ( 50 ) , isoproterenol ( 13 ) , LY294002 ( 53 ) , norepinephrine ( 13 ) , NPA ( 13 ) , okadaic_acid ( 13 ) , PTX ( 13 ) , raclopride ( 13 ) , siRNA ( 13 ) , U0126 ( 34 ) , WIN ( 13 )

Downstream Regulation
Effects of modification on Huntingtin:	activity, induced ( 39 , 45 ) , molecular association, regulation ( 39 , 45 )
Effects of modification on biological processes:	apoptosis, induced ( 14 ) , apoptosis, inhibited ( 1 , 50 , 52 , 53 ) , cytoskeletal reorganization ( 39 ) , signaling pathway regulation ( 13 )
Induce interaction with:	KIF5B (mouse) ( 45 ) , dynactin 1 (human) ( 39 )

Disease / Diagnostics Relevance
Relevant diseases:	Huntington's disease ( 2 , 8 , 39 )

References
1	Xu X, et al. (2020) pS421 huntingtin modulates mitochondrial phenotypes and confers neuroprotection in an HD hiPSC model. Cell Death Dis 11, 809 32978366 Curated Info
2	Jung T, et al. (2020) The Polyglutamine Expansion at the N-Terminal of Huntingtin Protein Modulates the Dynamic Configuration and Phosphorylation of the C-Terminal HEAT Domain. Structure 28, 1035-1050.e8 32668197 Curated Info
3	Bouhaddou M, et al. (2020) The Global Phosphorylation Landscape of SARS-CoV-2 Infection. Cell 182 32645325 Curated Info
4	Rea S, et al. (2020) Insulin and Exendin-4 Reduced Mutated Huntingtin Accumulation in Neuronal Cells. Front Pharmacol 11, 779 32547392 Curated Info
5	Tousley A, et al. (2019) Huntingtin associates with the actin cytoskeleton and α-actinin isoforms to influence stimulus dependent morphology changes. PLoS One 14, e0212337 30768638 Curated Info
6	Mertins P, et al. (2016) Proteogenomics connects somatic mutations to signalling in breast cancer. Nature 534, 55-62 27251275 Curated Info
7	Carrier M, et al. (2016) Phosphoproteome and Transcriptome of RA-Responsive and RA-Resistant Breast Cancer Cell Lines. PLoS One 11, e0157290 27362937 Curated Info
8	Naia L, et al. (2015) Activation of IGF-1 and Insulin Signaling Pathways Ameliorate Mitochondrial Function and Energy Metabolism in Huntington's Disease Human Lymphoblasts. Mol Neurobiol 51, 331-48 24841383 Curated Info
9	Huang B, et al. (2015) Scalable production in human cells and biochemical characterization of full-length normal and mutant huntingtin. PLoS One 10, e0121055 25799558 Curated Info
10	Sharma K, et al. (2014) Ultradeep human phosphoproteome reveals a distinct regulatory nature of Tyr and Ser/Thr-based signaling. Cell Rep 8, 1583-94 25159151 Curated Info
11	Mertins P, et al. (2014) Ischemia in tumors induces early and sustained phosphorylation changes in stress kinase pathways but does not affect global protein levels. Mol Cell Proteomics 13, 1690-704 24719451 Curated Info
12	Yi T, et al. (2014) Quantitative phosphoproteomic analysis reveals system-wide signaling pathways downstream of SDF-1/CXCR4 in breast cancer stem cells. Proc Natl Acad Sci U S A 111, E2182-90 24782546 Curated Info
13	Marion S, et al. (2014) Dopamine D2 receptor relies upon PPM/PP2C protein phosphatases to dephosphorylate huntingtin protein. J Biol Chem 289, 11715-24 24619418 Curated Info
14	Watkin EE, et al. (2014) Phosphorylation of mutant huntingtin at serine 116 modulates neuronal toxicity. PLoS One 9, e88284 24505464 Curated Info
15	Britton D, et al. (2014) Quantification of pancreatic cancer proteome and phosphorylome: indicates molecular events likely contributing to cancer and activity of drug targets. PLoS One 9, e90948 24670416 Curated Info
16	Schweppe DK, Rigas JR, Gerber SA (2013) Quantitative phosphoproteomic profiling of human non-small cell lung cancer tumors. J Proteomics 91, 286-96 23911959 Curated Info
17	Klammer M, et al. (2012) Phosphosignature predicts dasatinib response in non-small cell lung cancer. Mol Cell Proteomics 11, 651-68 22617229 Curated Info
18	Weber C, Schreiber TB, Daub H (2012) Dual phosphoproteomics and chemical proteomics analysis of erlotinib and gefitinib interference in acute myeloid leukemia cells. J Proteomics 75, 1343-56 22115753 Curated Info
19	Mulhern D (2011) CST Curation Set: 12832; Year: 2011; Biosample/Treatment: cell line, HEK 293/ku-0063794; Disease: -; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: RXXp[ST] Antibodies Used to Purify Peptides prior to LCMS: Phospho-Akt Substrate (RXRXXS/T) (23C8D2) Rabbit mAb Cat#: 10001, PTMScan(R) Phospho-Akt Substrate Motif (RXRXXS/T) Immunoaffinity Beads Cat#: 1979 Curated Info
20	Mulhern D (2011) CST Curation Set: 12836; Year: 2011; Biosample/Treatment: cell line, HEK 293/WYE-354; Disease: -; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: RXXp[ST] Antibodies Used to Purify Peptides prior to LCMS: Phospho-Akt Substrate (RXRXXS/T) (23C8D2) Rabbit mAb Cat#: 10001, PTMScan(R) Phospho-Akt Substrate Motif (RXRXXS/T) Immunoaffinity Beads Cat#: 1979 Curated Info
21	Mulhern D (2011) CST Curation Set: 12840; Year: 2011; Biosample/Treatment: cell line, HEK 293/untreated; Disease: -; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: RXXp[ST] Antibodies Used to Purify Peptides prior to LCMS: Phospho-Akt Substrate (RXRXXS/T) (23C8D2) Rabbit mAb Cat#: 10001, PTMScan(R) Phospho-Akt Substrate Motif (RXRXXS/T) Immunoaffinity Beads Cat#: 1979 Curated Info
22	Mulhern D (2011) CST Curation Set: 12841; Year: 2011; Biosample/Treatment: cell line, HEK 293/untreated; Disease: -; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: RXXp[ST] Antibodies Used to Purify Peptides prior to LCMS: Phospho-Akt Substrate (RXRXXS/T) (23C8D2) Rabbit mAb Cat#: 10001, PTMScan(R) Phospho-Akt Substrate Motif (RXRXXS/T) Immunoaffinity Beads Cat#: 1979 Curated Info
23	Hsu PP, et al. (2011) The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332, 1317-22 21659604 Curated Info
24	Moritz A (2011) CST Curation Set: 11939; Year: 2011; Biosample/Treatment: cell line, MKN-45/untreated; Disease: gastric carcinoma; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: RXXp[ST] Curated Info
25	Beausoleil S (2010) CST Curation Set: 10285; Year: 2010; Biosample/Treatment: cell line, K-562/untreated; Disease: chronic myelogenous leukemia; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: RXXp[ST] Curated Info
26	Beausoleil S (2010) CST Curation Set: 10278; Year: 2010; Biosample/Treatment: cell line, K-562/untreated; Disease: chronic myelogenous leukemia; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: RXXp[ST] Curated Info
27	Beausoleil S (2010) CST Curation Set: 10284; Year: 2010; Biosample/Treatment: cell line, K-562/untreated; Disease: chronic myelogenous leukemia; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: RXXp[ST] Curated Info
28	Beausoleil S (2010) CST Curation Set: 10280; Year: 2010; Biosample/Treatment: cell line, K-562/untreated; Disease: chronic myelogenous leukemia; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: RXXp[ST] Curated Info
29	Beausoleil S (2010) CST Curation Set: 10279; Year: 2010; Biosample/Treatment: cell line, K-562/untreated; Disease: chronic myelogenous leukemia; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: RXXp[ST] Curated Info
30	Christensen GL, et al. (2010) Quantitative phosphoproteomics dissection of seven-transmembrane receptor signaling using full and biased agonists. Mol Cell Proteomics 9, 1540-53 20363803 Curated Info
31	Possemato A (2010) CST Curation Set: 9630; Year: 2010; Biosample/Treatment: cell line, Jurkat/calyculin_A & pervanadate; Disease: T cell leukemia; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: RXXp[ST] Antibodies Used to Purify Peptides prior to LCMS: Phospho-Akt Substrate (RXRXXS/T) (110B7) Rabbit mAb Cat#: 9614, PTMScan(R) Phospho-Akt Substrate Motif (RXXS/T) Immunoaffinity Beads Cat#: 1978 Curated Info
32	Han G, et al. (2010) Phosphoproteome analysis of human liver tissue by long-gradient nanoflow LC coupled with multiple stage MS analysis. Electrophoresis 31, 1080-9 20166139 Curated Info
33	Moritz A, et al. (2010) Akt-RSK-S6 Kinase Signaling Networks Activated by Oncogenic Receptor Tyrosine Kinases. Sci Signal 3, ra64 20736484 Curated Info
34	Pan C, Olsen JV, Daub H, Mann M (2009) Global effects of kinase inhibitors on signaling networks revealed by quantitative phosphoproteomics. Mol Cell Proteomics 8, 2796-808 19651622 Curated Info
35	Gauci S, et al. (2009) Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach. Anal Chem 81, 4493-501 19413330 Curated Info
36	Moritz A (2009) CST Curation Set: 5895; Year: 2009; Biosample/Treatment: cell line, NCI-H1703/U 0126; Disease: non-small cell lung cancer; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: RXXp[ST] Antibodies Used to Purify Peptides prior to LCMS: Phospho-Akt Substrate (RXRXXS/T) (23C8D2) Rabbit mAb Cat#: 10001, PTMScan(R) Phospho-Akt Substrate Motif (RXRXXS/T) Immunoaffinity Beads Cat#: 1979 Curated Info
37	Moritz A (2009) CST Curation Set: 5889; Year: 2009; Biosample/Treatment: cell line, NCI-H1703/wortmannin; Disease: non-small cell lung cancer; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: RXXp[ST] Antibodies Used to Purify Peptides prior to LCMS: Phospho-Akt Substrate (RXRXXS/T) (23C8D2) Rabbit mAb Cat#: 10001, PTMScan(R) Phospho-Akt Substrate Motif (RXRXXS/T) Immunoaffinity Beads Cat#: 1979 Curated Info
38	Moritz A (2009) CST Curation Set: 5885; Year: 2009; Biosample/Treatment: cell line, NCI-H1703/Gleevec; Disease: non-small cell lung cancer; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: RXXp[ST] Antibodies Used to Purify Peptides prior to LCMS: Phospho-Akt Substrate (RXRXXS/T) (23C8D2) Rabbit mAb Cat#: 10001, PTMScan(R) Phospho-Akt Substrate Motif (RXRXXS/T) Immunoaffinity Beads Cat#: 1979 Curated Info
39	Zala D, et al. (2008) Phosphorylation of mutant huntingtin at S421 restores anterograde and retrograde transport in neurons. Hum Mol Genet 17, 3837-46 18772195 Curated Info
40	Moritz A (2008) CST Curation Set: 5652; Year: 2008; Biosample/Treatment: cell line, NCI-H3255/rapamycin; Disease: non-small cell lung cancer; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: RXXp[ST] Antibodies Used to Purify Peptides prior to LCMS: Phospho-Akt Substrate (RXRXXS/T) (23C8D2) Rabbit mAb Cat#: 10001, PTMScan(R) Phospho-Akt Substrate Motif (RXRXXS/T) Immunoaffinity Beads Cat#: 1979 Curated Info
41	Moritz A (2008) CST Curation Set: 5655; Year: 2008; Biosample/Treatment: cell line, NCI-H3255/Iressa; Disease: non-small cell lung cancer; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: RXXp[ST] Antibodies Used to Purify Peptides prior to LCMS: Phospho-Akt Substrate (RXRXXS/T) (23C8D2) Rabbit mAb Cat#: 10001, PTMScan(R) Phospho-Akt Substrate Motif (RXRXXS/T) Immunoaffinity Beads Cat#: 1979 Curated Info
42	Moritz A (2008) CST Curation Set: 5450; Year: 2008; Biosample/Treatment: cell line, NCI-H1703/rapamycin; Disease: non-small cell lung cancer; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: RXXp[ST] Antibodies Used to Purify Peptides prior to LCMS: Phospho-Akt Substrate (RXRXXS/T) (23C8D2) Rabbit mAb Cat#: 10001, PTMScan(R) Phospho-Akt Substrate Motif (RXRXXS/T) Immunoaffinity Beads Cat#: 1979 Curated Info
43	Moritz A (2008) CST Curation Set: 5445; Year: 2008; Biosample/Treatment: cell line, NCI-H1703/U 0126; Disease: non-small cell lung cancer; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: RXXp[ST] Antibodies Used to Purify Peptides prior to LCMS: Phospho-Akt Substrate (RXRXXS/T) (23C8D2) Rabbit mAb Cat#: 10001, PTMScan(R) Phospho-Akt Substrate Motif (RXRXXS/T) Immunoaffinity Beads Cat#: 1979 Curated Info
44	Moritz A (2008) CST Curation Set: 5016; Year: 2008; Biosample/Treatment: cell line, NCI-H1703/Gleevec; Disease: non-small cell lung cancer; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: RXXp[ST] Antibodies Used to Purify Peptides prior to LCMS: Phospho-Akt Substrate (RXRXXS/T) (23C8D2) Rabbit mAb Cat#: 10001, PTMScan(R) Phospho-Akt Substrate Motif (RXRXXS/T) Immunoaffinity Beads Cat#: 1979 Curated Info
45	Colin E, et al. (2008) Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport in neurons. EMBO J 27, 2124-34 18615096 Curated Info
46	Zahedi RP, et al. (2008) Phosphoproteome of resting human platelets. J Proteome Res 7, 526-34 18088087 Curated Info
47	Moritz A (2007) CST Curation Set: 2906; Year: 2007; Biosample/Treatment: cell line, K562/-; Disease: chronic myelogenous leukemia; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: RXXp[ST] Antibodies Used to Purify Peptides prior to LCMS: Phospho-Akt Substrate (RXRXXT-P) (81E12B5) Rabbit mAb Cat#: 10003 Curated Info
48	Beausoleil SA, et al. (2006) A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nat Biotechnol 24, 1285-92 16964243 Curated Info
49	Schilling B, et al. (2006) Huntingtin phosphorylation sites mapped by mass spectrometry. Modulation of cleavage and toxicity. J Biol Chem 281, 23686-97 16782707 Curated Info
50	Pardo R, et al. (2006) Inhibition of calcineurin by FK506 protects against polyglutamine-huntingtin toxicity through an increase of huntingtin phosphorylation at S421. J Neurosci 26, 1635-45 16452687 Curated Info
51	Warby SC, et al. (2005) Huntingtin phosphorylation on serine 421 is significantly reduced in the striatum and by polyglutamine expansion in vivo. Hum Mol Genet 14, 1569-77 15843398 Curated Info
52	Rangone H, et al. (2004) The serum- and glucocorticoid-induced kinase SGK inhibits mutant huntingtin-induced toxicity by phosphorylating serine 421 of huntingtin. Eur J Neurosci 19, 273-9 14725621 Curated Info
53	Humbert S, et al. (2002) The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt. Dev Cell 2, 831-7 12062094 Curated Info