PUBLICATION

A long isoform of GIV/Girdin contains a PDZ-binding module that regulates localization and G-protein binding

Authors

Ear, J., Abd El-Hafeez, A.A., Roy, S., Ngo, T., Rajapakse, N., Choi, J., Khandelwal, S., Ghassemian, M., McCaffrey, L., Kufareva, I., Sahoo, D., Ghosh, P.

ID

ZDB-PUB-210910-18

Date

2021

Source

The Journal of biological chemistry 296: 100493 (Journal)

Registered Authors

Keywords

cancer, cell biology, cell junctions, cell signaling, protein interactions

MeSH Terms

Protein Binding
Protein Transport
Zebrafish
Animals
Cell Line
Humans
Guanine Nucleotide Exchange Factors/metabolism*
Vesicular Transport Proteins/chemistry
Vesicular Transport Proteins/metabolism*
Colonic Neoplasms/genetics
Colonic Neoplasms/metabolism*
Colonic Neoplasms/pathology
Microfilament Proteins/chemistry
Microfilament Proteins/metabolism*
GTP-Binding Protein alpha Subunits, Gi-Go/metabolism*
Cell Proliferation
Phosphorylation
Signal Transduction
PDZ Domains
Protein Isoforms
Cell Line, Tumor/physiology

(all 21)

PubMed

33675748 Full text @ J. Biol. Chem.

Abstract

PDZ domains are one of the most abundant protein domains in eukaryotes and are frequently found on junction-localized scaffold proteins. Various signaling molecules bind to PDZ proteins via PDZ-binding motifs (PBM) and fine-tune cellular signaling. However, how such interaction affects protein function is difficult to predict and must be solved empirically. Here we describe a long isoform of the guanine nucleotide exchange factor GIV/Girdin (CCDC88A) that we named GIV-L, which is conserved throughout evolution, from invertebrates to vertebrates, and contains a PBM. Unlike GIV, which lacks PBM and is cytosolic, GIV-L localizes onto cell junctions and has a PDZ interactome (as shown through annotating Human Cell Map and BioID-proximity labeling studies), which impacts GIV-L's ability to bind and activate trimeric G-protein, Gαi, through its guanine-nucleotide exchange modulator (GEM) module. This GEM module is found exclusively in vertebrates. We propose that the two functional modules in GIV may have 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 analysis 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 regulation in GIV/CCDC88A transcript helps to achieve protein modularity, which allows the protein to play opposing roles either as a tumor suppressor (GIV-L) or as an oncogene (GIV).

Genes / Markers

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