About Girdin

Here is a few things about Girdin.

Girdin (Girders of actin filament) is also known as:
Akt phosphorylation enhancer (APE),
Coiled-coil domain-containing protein 88A,
G alpha-interacting vesicle-associated protein (GIV),
Hook-related protein 1 (HkPP1).

Girdin is a large protein (1871 amino acid lengths) which forms homodimer, whereby it potentially engages in multiple interactions. It is expressed broadly (Enomoto et al. 2005). It has a guanine nucleotide exchange factor (GEF) motif that associate preferentially with Gαi (Garcia-Marcos, Ghosh, & Farquhar 2009).

Girdin interacts with:

Akt1 (a.k.a. protein kinase B) to enhance its kinase action. Girdin itself does not have a kinase activity.

Cytoskeletal proteins: microtubules, actin.

Disrupted in schizophrenia 1 (DISC1) which is involved in proliferation of neural progenitor cells during brain development and in adult neurogenesis in dentate gyrus.

Dynamin, a GTPase.

Gαi/0; the amino acid residues (178 - 270) of Gαi3 favour Girdin associating with Gαi3 over Gα0 (Garcia-Marcos, Ghosh & Farquhar 2010).

GPCRs: lysophosphatidic acid receptor (LPAR), formylmethionylleucylphenylalanine receptor (fMLPR).

Phosphatidylinositol 4-phosphate (PI4P), also weakly with phosphatidylinositol 3-phosphate (PI3P).

Receptor Tyrosine Kinases: EGFR, IGFR1, VEGFR.

Garcia-Marcos et al. has presented a working model of protein interaction map around Girdin and Gαi (2011. Figure 7. p.682).


Notable activities:

It can be activated by phosphorylation by epidermal growth factor (EGF) through the action of phosphoinositide 3-kinase (PI3K) or by Akt.

It promotes cell migration through interactions with Akt and actin (Enomoto et al. 2005; Garcia-Marcos, Ghosh & Farquhar 2010). Girdin-Gαi3 was shown to induce migration in mammalian cell by enhancing Akt and remodelling the actin cytoskeleton (Ghosh et al. 2008).

In a combined effort, activator of G-protein signalling 3 (AGS3), Gαi3, and Girdin regulates autophagy through PI3K and Akt (Garcia-Marcos et al. 2011).

With its versatile binding property, Girdin homodimers could act as adaptors joining two separate functional proteins; this indicates its possible regulatory roles in cellular processes initiated by GPCRs, of Gαi-coupled in particular. For instance, by forming a multimer including dynamin, Girdin might initiate the internalisation of receptors by directly interacting receptors at the same time, or by interacting with Gαi present nearby the Gαi-coupled receptors. Clarifying how Girdin could regulate functions of Gαi-coupled receptors would reveal another mechanism of cellular regulation of the receptor pharmacology in detail, as well as providing another component for the intracellular signalling network involving GPCRs.


References

Enomoto A et al. 2005. Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev Cell. 9: 389-402.

Garcia-Marcos M, Ghosh P, & Farquhar MG. 2009. GIV is a nonreceptor GEF for Gαi with a unique motif that regulates Akt signaling. PNAS 106: 3178–3183.

Garcia-Marcos M et al. 2010. A Structural Determinant That Renders Gαi Sensitive to
Activation by GIV/Girdin Is Required to Promote Cell Migration. J Bio Chem. 285: 12765–12777.

Garcia-Marcos M et al. 2011. A GDI (AGS3) and a GEF (GIV) regulate autophagy by balancing G protein activity and growth factor signals. MBoC. 22: 673-686.

Ghosh P et al. 2008. Activation of Gαi3 triggers cell migration via regulation of GIV. J. Cell Biol. 182: 381–393.