FGD1 as a central regulator of extracellular matrix remodelling – lessons from faciogenital dysplasia

Abstract

SummaryDisabling mutations in the FGD1 gene cause faciogenital dysplasia (also known as Aarskog-Scott syndrome), a human X-linked developmental disorder that results in disproportionately short stature, facial, skeletal and urogenital anomalies, and in a number of cases, mild mental retardation. FGD1 encodes the guanine nucleotide exchange factor FGD1, which is specific for the Rho GTPase cell division cycle 42 (CDC42). CDC42 controls cytoskeleton-dependent membrane rearrangements, transcriptional activation, secretory membrane trafficking, G1 transition during the cell cycle and tumorigenic transformation. The cellular mechanisms by which FGD1 mutations lead to the hallmark skeletal deformations of faciogenital dysplasia remain unclear, but the pathology of the disease, as well as some recent discoveries, clearly show that the protein is involved in the regulation of bone development. Two recent studies unveiled new potential functions of FGD1, in particular, its involvement in the regulation of the formation and function of invadopodia and podosomes, which are cellular structures devoted to degradation of the extracellular matrix in tumour and endothelial cells. Here, we discuss the hypothesis that FGD1 might be an important regulator of events controlling extracellular matrix remodelling and possibly cell invasion in physiological and pathological settings. Additionally, we focus on how studying the cell biology of FGD1 might help us to connect the dots that link CDC42 signalling with remodelling of the extracellular matrix (ECM) in physiology and complex diseases, while, at the same time, furthering our understanding of the pathogenesis of faciogenital dysplasia.

Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease

“…The ASS-associated FGD1 mutations cause loss-of-function (deletion, nonsense mutations causing expression of truncated proteins, missense mutations in DH-PH domains) and account for ~20% of individuals with ASS. 130,131 …”

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

“…FGD1 activates MAP3K mixedlineage kinase 3 (MLK3), which regulates ERK and p38 MAPK, which in turn phosphorylate and activate the master regulator of osteoblast differentiation, RUNX2 (163). FGD1 is involved in the regulation of the formation and function of invadopodia and podosomes, which are cellular structures devoted to degradation of the extracellular matrix in tumour and endothelial cells (164).…”

Integration of signaling and cytoskeletal remodeling by Nck in directional cell migration

“…Our recently published studies show that Nck modulates the polarized activation of Cdc42 in migrating cells 55 . In addition, faciogenital dysplasia protein 1 (FGD1), a cortactin binding partner 109 and Cdc42 GEF involved in post-Golgi cargo trafficking, 110 has been implicated in invadopodia biogenesis and regulation of extracellular matrix remodeling 111 , 112 . Whether the cortactin/Nck signaling axis modulates the Cdc42/MT1-MMP reciprocity during vascular morphogenesis remains an unanswered question.…”