{"gene":"STK11IP","run_date":"2026-06-10T07:46:43","timeline":{"discoveries":[{"year":2022,"finding":"mTORC1 phosphorylates STK11IP at Ser404 on the lysosome surface. STK11IP knockout leads to a robust increase in autophagy flux, and dephosphorylation of STK11IP at Ser404 represses its role as an autophagy inhibitor. Mechanistically, STK11IP binds to V-ATPase and regulates V-ATPase activity, thereby controlling lysosomal acidification.","method":"Quantitative phosphoproteomic cross-reference of lysosome proteome with mTORC1-regulated phosphoproteome; STK11IP knockout mice; in vitro and in vivo autophagy flux assays; co-immunoprecipitation of STK11IP with V-ATPase; phosphomutant analysis (Ser404)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (phosphoproteomics, KO mice, co-IP, mutagenesis, functional flux assays) in a single rigorous study establishing substrate identity, binding partner, and functional consequence","pmids":["35365663"],"is_preprint":false},{"year":2021,"finding":"LKB1IP (STK11IP) promotes pathological cardiac hypertrophy by directly targeting PTEN and inhibiting its phosphatase activity, thereby activating Akt signalling. LKB1IP knockout protected mice from ISO- or TAC-induced cardiac hypertrophy and fibrosis, while overexpression aggravated ISO-induced cardiomyocyte hypertrophy in vitro.","method":"LKB1IP knockout mice challenged with ISO injection or TAC surgery; cardiac function, hypertrophy and fibrosis measured; LKB1IP overexpression and siRNA knockdown in cardiomyocytes; direct targeting of PTEN and inhibition of its phosphatase activity assayed","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice with defined phenotype plus in vitro gain/loss-of-function and mechanistic targeting of PTEN phosphatase activity, single lab","pmids":["33486894"],"is_preprint":false},{"year":2026,"finding":"VASN (vasorin) interacts with lysosomal mTOR and STK11IP, and disrupts the binding of STK11IP to mTOR and V-ATPase, thereby relieving STK11IP-mediated suppression of lysosomal acidification. This places STK11IP as a negative regulator of V-ATPase activity downstream of mTOR, whose function can be antagonised by VASN.","method":"Co-immunoprecipitation (lysosomal IP, DSP crosslinking); co-localization imaging; functional lysosomal acidification assays; binding competition experiments between VASN, STK11IP, mTOR, and V-ATPase","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and functional acidification assays in a single lab, providing mechanistic context for STK11IP–V-ATPase interaction identified previously","pmids":["41630427"],"is_preprint":false},{"year":2020,"finding":"siRNA-mediated knockdown of STK11IP in melanoma cell line A375 did not significantly affect cell viability or proliferation, but accelerated cell migration speed in wound healing assays.","method":"siRNA knockdown; MTT viability assay (negative result for viability); wound healing migration assay (positive result for accelerated migration)","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single cell line, phenotypic readout without pathway placement; viability result is negative","pmids":["33041669"],"is_preprint":false}],"current_model":"STK11IP (LKB1IP) is a lysosome-localised protein that is phosphorylated by mTORC1 at Ser404; in its phosphorylated state it binds V-ATPase and suppresses its activity to limit lysosomal acidification and autophagy flux, while VASN can disrupt the STK11IP–mTOR–V-ATPase complex to relieve this inhibition; outside the lysosome, STK11IP promotes pathological cardiac hypertrophy by directly inhibiting PTEN phosphatase activity and thereby activating Akt signalling."},"narrative":{"mechanistic_narrative":"STK11IP (LKB1IP) is a lysosome-associated regulator of autophagy that couples mTORC1 signalling to control of lysosomal acidification [PMID:35365663]. On the lysosome surface, mTORC1 phosphorylates STK11IP at Ser404, and in this phosphorylated state STK11IP binds V-ATPase and suppresses its activity, thereby limiting lysosomal acidification and restraining autophagy flux; loss of STK11IP or dephosphorylation of Ser404 de-represses autophagy [PMID:35365663]. This inhibitory STK11IP–mTOR–V-ATPase assembly is antagonised by VASN, which interacts with lysosomal mTOR and STK11IP and disrupts STK11IP binding to mTOR and V-ATPase, relieving the suppression of acidification [PMID:41630427]. Beyond the lysosome, STK11IP directly inhibits PTEN phosphatase activity to activate Akt signalling and drives pathological cardiac hypertrophy, as STK11IP knockout protects mice from ISO- and TAC-induced hypertrophy and fibrosis [PMID:33486894].","teleology":[{"year":2021,"claim":"Established a non-lysosomal, pro-pathological role for STK11IP by showing it directly inhibits PTEN to drive Akt-dependent cardiac hypertrophy.","evidence":"LKB1IP knockout mice challenged with ISO or TAC, plus cardiomyocyte gain/loss-of-function and PTEN phosphatase activity assays","pmids":["33486894"],"confidence":"Medium","gaps":["Single lab; mechanism of direct PTEN inhibition not structurally defined","Relationship between this PTEN-targeting role and the lysosomal V-ATPase function is unaddressed","No structural basis for STK11IP–PTEN interaction"]},{"year":2022,"claim":"Defined STK11IP as a direct mTORC1 substrate (Ser404) that gates autophagy by binding and suppressing V-ATPase to limit lysosomal acidification.","evidence":"Lysosomal phosphoproteomics cross-referenced with mTORC1 targets, STK11IP knockout mice, autophagy flux assays, co-IP with V-ATPase, and Ser404 phosphomutants","pmids":["35365663"],"confidence":"High","gaps":["Which V-ATPase subunit STK11IP contacts is not resolved","Phosphatase responsible for Ser404 dephosphorylation not identified","Stoichiometry and structure of the STK11IP–V-ATPase interaction unknown"]},{"year":2026,"claim":"Placed STK11IP within a regulatable module by identifying VASN as an antagonist that disrupts STK11IP binding to mTOR and V-ATPase to relieve acidification suppression.","evidence":"Lysosomal co-IP with DSP crosslinking, co-localization imaging, binding-competition assays, and lysosomal acidification readouts","pmids":["41630427"],"confidence":"Medium","gaps":["Single lab; reciprocal validation of the VASN displacement mechanism in vivo not shown","How VASN access to lysosomal STK11IP is controlled is unknown","Whether VASN antagonism intersects the PTEN/cardiac axis is untested"]},{"year":null,"claim":"Whether the lysosomal V-ATPase regulatory role and the PTEN-inhibitory cardiac role reflect one integrated mechanism or distinct activities remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No study links STK11IP's autophagy/V-ATPase function to its PTEN/Akt function","Domain architecture mediating the distinct interactions is uncharacterized","Tissue-specific determinants of which role dominates are unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0]}],"complexes":[],"partners":["V-ATPASE","MTOR","VASN","PTEN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N1F8","full_name":"Serine/threonine-protein kinase 11-interacting protein","aliases":["LKB1-interacting protein 1"],"length_aa":1088,"mass_kda":120.3,"function":"May regulate STK11/LKB1 function by controlling its subcellular localization","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8N1F8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STK11IP","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TMEM106B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/STK11IP","total_profiled":1310},"omim":[{"mim_id":"607172","title":"SERINE/THREONINE KINASE 11-INTERACTING PROTEIN; STK11IP","url":"https://www.omim.org/entry/607172"},{"mim_id":"175200","title":"PEUTZ-JEGHERS SYNDROME; PJS","url":"https://www.omim.org/entry/175200"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Vesicles","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/STK11IP"},"hgnc":{"alias_symbol":["LIP1","KIAA1898","LKB1IP","STK11IP1"],"prev_symbol":[]},"alphafold":{"accession":"Q8N1F8","domains":[{"cath_id":"3.80.10.10","chopping":"2-53_71-263","consensus_level":"medium","plddt":85.4658,"start":2,"end":263},{"cath_id":"2.30.29.30","chopping":"537-592_611-659","consensus_level":"high","plddt":84.479,"start":537,"end":659},{"cath_id":"2.30.29.30","chopping":"783-924","consensus_level":"high","plddt":84.1563,"start":783,"end":924},{"cath_id":"2.30.29.30","chopping":"939-981_1008-1082","consensus_level":"high","plddt":85.8332,"start":939,"end":1082}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N1F8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N1F8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N1F8-F1-predicted_aligned_error_v6.png","plddt_mean":67.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STK11IP","jax_strain_url":"https://www.jax.org/strain/search?query=STK11IP"},"sequence":{"accession":"Q8N1F8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N1F8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N1F8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N1F8"}},"corpus_meta":[{"pmid":"12438709","id":"PMC_12438709","title":"Search for the second Peutz-Jeghers syndrome locus: exclusion of the STK13, PRKCG, KLK10, and PSCD2 genes on chromosome 19 and the STK11IP gene on chromosome 2.","date":"2002","source":"Cytogenetic and genome research","url":"https://pubmed.ncbi.nlm.nih.gov/12438709","citation_count":45,"is_preprint":false},{"pmid":"22127005","id":"PMC_22127005","title":"Presence of histone H3 acetylated at lysine 9 in male germ cells and its distribution pattern in the genome of human spermatozoa.","date":"2011","source":"Reproduction, fertility, and development","url":"https://pubmed.ncbi.nlm.nih.gov/22127005","citation_count":45,"is_preprint":false},{"pmid":"34487971","id":"PMC_34487971","title":"The immune microenvironment in EGFR- and ERBB2-mutated lung adenocarcinoma.","date":"2021","source":"ESMO open","url":"https://pubmed.ncbi.nlm.nih.gov/34487971","citation_count":33,"is_preprint":false},{"pmid":"35365663","id":"PMC_35365663","title":"Quantitative phosphoproteomic analyses identify STK11IP as a lysosome-specific substrate of mTORC1 that regulates lysosomal acidification.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35365663","citation_count":19,"is_preprint":false},{"pmid":"30297789","id":"PMC_30297789","title":"Typing tumors using pathways selected by somatic evolution.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30297789","citation_count":16,"is_preprint":false},{"pmid":"33486894","id":"PMC_33486894","title":"LKB1IP promotes pathological cardiac hypertrophy by targeting PTEN/Akt signalling pathway.","date":"2021","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33486894","citation_count":15,"is_preprint":false},{"pmid":"37540954","id":"PMC_37540954","title":"Comparison of symmetrical and asymmetrical cleavage 2-cell embryos of porcine by Smart-seq2.","date":"2023","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/37540954","citation_count":4,"is_preprint":false},{"pmid":"33041669","id":"PMC_33041669","title":"Analysis of candidate genes expected to be essential for melanoma surviving.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/33041669","citation_count":3,"is_preprint":false},{"pmid":"39895895","id":"PMC_39895895","title":"Lobular endocervical glandular hyperplasia diagnosed during surveillance for Peutz-Jeghers Syndrome: A case report.","date":"2025","source":"Gynecologic oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/39895895","citation_count":1,"is_preprint":false},{"pmid":"41630427","id":"PMC_41630427","title":"TGFB-inducible VASN (vasorin) promotes lysosomal acidification.","date":"2026","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/41630427","citation_count":0,"is_preprint":false},{"pmid":"41618999","id":"PMC_41618999","title":"Cell-free DNA in chemical carcinogen induced mouse lung cancer and colon cancer model: its implications in diagnostics and therapeutics.","date":"2026","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/41618999","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8715,"output_tokens":1225,"usd":0.02226,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7839,"output_tokens":1731,"usd":0.041235,"stage2_stop_reason":"end_turn"},"total_usd":0.063495,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"mTORC1 phosphorylates STK11IP at Ser404 on the lysosome surface. STK11IP knockout leads to a robust increase in autophagy flux, and dephosphorylation of STK11IP at Ser404 represses its role as an autophagy inhibitor. Mechanistically, STK11IP binds to V-ATPase and regulates V-ATPase activity, thereby controlling lysosomal acidification.\",\n      \"method\": \"Quantitative phosphoproteomic cross-reference of lysosome proteome with mTORC1-regulated phosphoproteome; STK11IP knockout mice; in vitro and in vivo autophagy flux assays; co-immunoprecipitation of STK11IP with V-ATPase; phosphomutant analysis (Ser404)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (phosphoproteomics, KO mice, co-IP, mutagenesis, functional flux assays) in a single rigorous study establishing substrate identity, binding partner, and functional consequence\",\n      \"pmids\": [\"35365663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LKB1IP (STK11IP) promotes pathological cardiac hypertrophy by directly targeting PTEN and inhibiting its phosphatase activity, thereby activating Akt signalling. LKB1IP knockout protected mice from ISO- or TAC-induced cardiac hypertrophy and fibrosis, while overexpression aggravated ISO-induced cardiomyocyte hypertrophy in vitro.\",\n      \"method\": \"LKB1IP knockout mice challenged with ISO injection or TAC surgery; cardiac function, hypertrophy and fibrosis measured; LKB1IP overexpression and siRNA knockdown in cardiomyocytes; direct targeting of PTEN and inhibition of its phosphatase activity assayed\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice with defined phenotype plus in vitro gain/loss-of-function and mechanistic targeting of PTEN phosphatase activity, single lab\",\n      \"pmids\": [\"33486894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"VASN (vasorin) interacts with lysosomal mTOR and STK11IP, and disrupts the binding of STK11IP to mTOR and V-ATPase, thereby relieving STK11IP-mediated suppression of lysosomal acidification. This places STK11IP as a negative regulator of V-ATPase activity downstream of mTOR, whose function can be antagonised by VASN.\",\n      \"method\": \"Co-immunoprecipitation (lysosomal IP, DSP crosslinking); co-localization imaging; functional lysosomal acidification assays; binding competition experiments between VASN, STK11IP, mTOR, and V-ATPase\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and functional acidification assays in a single lab, providing mechanistic context for STK11IP–V-ATPase interaction identified previously\",\n      \"pmids\": [\"41630427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"siRNA-mediated knockdown of STK11IP in melanoma cell line A375 did not significantly affect cell viability or proliferation, but accelerated cell migration speed in wound healing assays.\",\n      \"method\": \"siRNA knockdown; MTT viability assay (negative result for viability); wound healing migration assay (positive result for accelerated migration)\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single cell line, phenotypic readout without pathway placement; viability result is negative\",\n      \"pmids\": [\"33041669\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STK11IP (LKB1IP) is a lysosome-localised protein that is phosphorylated by mTORC1 at Ser404; in its phosphorylated state it binds V-ATPase and suppresses its activity to limit lysosomal acidification and autophagy flux, while VASN can disrupt the STK11IP–mTOR–V-ATPase complex to relieve this inhibition; outside the lysosome, STK11IP promotes pathological cardiac hypertrophy by directly inhibiting PTEN phosphatase activity and thereby activating Akt signalling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STK11IP (LKB1IP) is a lysosome-associated regulator of autophagy that couples mTORC1 signalling to control of lysosomal acidification [#0]. On the lysosome surface, mTORC1 phosphorylates STK11IP at Ser404, and in this phosphorylated state STK11IP binds V-ATPase and suppresses its activity, thereby limiting lysosomal acidification and restraining autophagy flux; loss of STK11IP or dephosphorylation of Ser404 de-represses autophagy [#0]. This inhibitory STK11IP–mTOR–V-ATPase assembly is antagonised by VASN, which interacts with lysosomal mTOR and STK11IP and disrupts STK11IP binding to mTOR and V-ATPase, relieving the suppression of acidification [#2]. Beyond the lysosome, STK11IP directly inhibits PTEN phosphatase activity to activate Akt signalling and drives pathological cardiac hypertrophy, as STK11IP knockout protects mice from ISO- and TAC-induced hypertrophy and fibrosis [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Established a non-lysosomal, pro-pathological role for STK11IP by showing it directly inhibits PTEN to drive Akt-dependent cardiac hypertrophy.\",\n      \"evidence\": \"LKB1IP knockout mice challenged with ISO or TAC, plus cardiomyocyte gain/loss-of-function and PTEN phosphatase activity assays\",\n      \"pmids\": [\"33486894\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single lab; mechanism of direct PTEN inhibition not structurally defined\",\n        \"Relationship between this PTEN-targeting role and the lysosomal V-ATPase function is unaddressed\",\n        \"No structural basis for STK11IP–PTEN interaction\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined STK11IP as a direct mTORC1 substrate (Ser404) that gates autophagy by binding and suppressing V-ATPase to limit lysosomal acidification.\",\n      \"evidence\": \"Lysosomal phosphoproteomics cross-referenced with mTORC1 targets, STK11IP knockout mice, autophagy flux assays, co-IP with V-ATPase, and Ser404 phosphomutants\",\n      \"pmids\": [\"35365663\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Which V-ATPase subunit STK11IP contacts is not resolved\",\n        \"Phosphatase responsible for Ser404 dephosphorylation not identified\",\n        \"Stoichiometry and structure of the STK11IP–V-ATPase interaction unknown\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placed STK11IP within a regulatable module by identifying VASN as an antagonist that disrupts STK11IP binding to mTOR and V-ATPase to relieve acidification suppression.\",\n      \"evidence\": \"Lysosomal co-IP with DSP crosslinking, co-localization imaging, binding-competition assays, and lysosomal acidification readouts\",\n      \"pmids\": [\"41630427\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single lab; reciprocal validation of the VASN displacement mechanism in vivo not shown\",\n        \"How VASN access to lysosomal STK11IP is controlled is unknown\",\n        \"Whether VASN antagonism intersects the PTEN/cardiac axis is untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the lysosomal V-ATPase regulatory role and the PTEN-inhibitory cardiac role reflect one integrated mechanism or distinct activities remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No study links STK11IP's autophagy/V-ATPase function to its PTEN/Akt function\",\n        \"Domain architecture mediating the distinct interactions is uncharacterized\",\n        \"Tissue-specific determinants of which role dominates are unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"V-ATPase\", \"MTOR\", \"VASN\", \"PTEN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}