Evolution of Modularity, Interactome and Functions of GIV/Girdin (CCDC88A) from Invertebrates to Vertebrates
Evolution of Modularity, Interactome and Functions of GIV/Girdin (CCDC88A) from Invertebrates to Vertebrates
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 guanine-nucleotide exchange modulator (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).
Ali Abd El-Hafeez Amer、Rajapakse Navin、Ghassemian Majid、Sahoo Debashis、Khandelwal Soni、Ear Jason、Choi Julie、Roy Suchismita、Kufareva Irina、Ghosh Pradipta、McCaffrey Luke、Ngo Tony
Department of Cellular and Molecular Medicine, University of California San DiegoDepartment of Cellular and Molecular Medicine, University of California San DiegoDepartment of Chemistry and Biochemistry, University of California San DiegoDepartment of Pediatrics, University of California San DiegoDepartment of Pediatrics, University of California San DiegoDepartment of Cellular and Molecular Medicine, University of California San Diego||Biological Sciences Department, California State Polytechnic UniversityDepartment of Cellular and Molecular Medicine, University of California San DiegoSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San DiegoSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San DiegoDepartment of Cellular and Molecular Medicine, University of California San Diego||Department of Medicine, University of California San Diego||Rebecca and John Moore Comprehensive Cancer Center, University of California San Diego||Veterans Affairs Medical CenterRosalind and Morris Goodman Cancer Research Centre, McGill University||Gerald Bronfman Department of Oncology, McGill UniversitySkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego
基础医学分子生物学细胞生物学
Cell junctionsCell signalingProtein InteractionsCancerCell Biology
Ali Abd El-Hafeez Amer,Rajapakse Navin,Ghassemian Majid,Sahoo Debashis,Khandelwal Soni,Ear Jason,Choi Julie,Roy Suchismita,Kufareva Irina,Ghosh Pradipta,McCaffrey Luke,Ngo Tony.Evolution of Modularity, Interactome and Functions of GIV/Girdin (CCDC88A) from Invertebrates to Vertebrates[EB/OL].(2025-03-28)[2025-05-18].https://www.biorxiv.org/content/10.1101/2020.09.28.317172.点此复制
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