{"doi":"10.1101/2020.09.28.317172","title":"Evolution of Modularity, Interactome and Functions of GIV/Girdin (CCDC88A) from Invertebrates to Vertebrates","abstract":"Abstract PDZ domains are one of the most abundant protein domains in eukaryotes and frequently found on junction-localized scaffold proteins. Various signaling molecules bind to PDZ proteins via PDZ-binding motifs (PBM) and finetune cellular signaling. Here we describe the presence of a PBM on GIV/Girdin (CCDC88A) that is conserved throughout evolution, from invertebrates to vertebrates, and is generated as a long isoform-variant in humans, which we named GIV-L . Unlike GIV, which lacks PBM and is cytosolic, GIV-L localizes to the cell junctions, and has a unique PDZ-interactome, which impacts GIV-L ’s ability to bind and activate trimeric G-protein, Gi through its g uanine-nucleotide e xchange m odulator (GEM) module; the GEM module is found exclusively in vertebrates. Thus, the two functional modules in GIV evolved sequentially: the ability to bind PDZ proteins via the PBM evolved earlier in invertebrates, whereas G-protein binding and activation may have evolved later only among vertebrates. Phenotypic studies in Caco-2 cells revealed that GIV and GIV-L may have antagonistic effects on cell growth, proliferation (cell cycle), and survival. Immunohistochemical analyses in human colon tissues showed that GIV expression increases with a concomitant decrease in GIV-L during cancer initiation. Taken together, these findings reveal how GIV/CCDC88A in humans displays evolutionary flexibility in modularity, which allows the resultant isoforms to play opposing roles either as a tumor suppressor (GIV-L) or as an oncogene (GIV).","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":131067,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9524,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":348400,"name":"Amer Ali Abd El‐Hafeez","orcid":"0000-0002-4822-6581","position":1,"is_corresponding":false},{"id":382453,"name":"Suchismita Roy","orcid":"0000-0002-6091-2357","position":2,"is_corresponding":false},{"id":354097,"name":"Tony Ngo","orcid":"0000-0002-6779-2546","position":3,"is_corresponding":false},{"id":382452,"name":"Navin Rajapakse","orcid":"0009-0005-0579-9645","position":4,"is_corresponding":false},{"id":428592,"name":"Julie Choi","orcid":"0000-0002-5670-9807","position":5,"is_corresponding":false},{"id":557141,"name":"Soni Khandelwal","orcid":"0000-0002-5431-3809","position":6,"is_corresponding":false},{"id":369191,"name":"Majid Ghassemian","orcid":"0000-0003-1026-5152","position":7,"is_corresponding":false},{"id":584412,"name":"Luke McCaffrey","orcid":"0000-0002-1754-8828","position":8,"is_corresponding":false},{"id":354098,"name":"Irina Kufareva","orcid":"0000-0001-9083-7039","position":9,"is_corresponding":false},{"id":294966,"name":"Debashis Sahoo","orcid":"0000-0003-2329-8228","position":10,"is_corresponding":false},{"id":294967,"name":"Pradipta Ghosh","orcid":"0000-0002-8917-3201","position":11,"is_corresponding":false},{"id":411572,"name":"Jason Ear","orcid":"0000-0002-8580-7748","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-18T23:16:00.235845Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}