Role of FGD1, a Cdc42 Guanine Nucleotide Exchange Factor, in Epidermal Growth Factor-Stimulated c-Jun NH2-Terminal Kinase Activation and Cell Migration

Abstract

Cell migration is an essential process involved in development, wound healing, tumor invasion, and metastasis. In migrating cells, re-organization of the actin cytoskeleton occurs dynamically to provide the force for cell motility. The Rho family small guanosine 5Ј-triphosphate (GTP)-binding proteins (G-proteins), consisting mainly of the Rho, Rac, and Cdc42 subfamilies, are key molecular switches that regulate various actin cytoskeleton-dependent cell functions, including cell shape change, cell migration, cell adhesion, and cytokinesis.1-3) Like all G-proteins, Rho family proteins act as binary switches by cycling between an inactive (guanosine 5Ј-diphosphate (GDP)-bound) and an active (GTP-bound) conformation state.Guanine nucleotide exchange factors (GEFs) stimulate the exchange of GDP for GTP to generate active forms of Rho proteins, whereas GTPase-activating proteins (GAPs) accelerate the intrinsic GTPase activity of Rho proteins to inactivate the switch. In theory, the active state of Rho proteins may be obtained through stimulation of a GEF or inhibition of a GAP, however, most evidence indicates that GEFs are the critical mediators for the activation of Rho proteins. 4)FGD1, a GEF for Cdc42, was originally identified and characterized by positional cloning in a family in which the phenotype of the developmental disorder (known as the faciogenital dysplasia or Aarskog-Scott syndrome; AAS) was associated with an X; 8 translocation.5,6) Further genetic analyses revealed that different types of point mutations occurred in FGD1 are also responsible for AAS.7) While most mutations were found in the DH domain or adjacent PH domain of FGD1, Orrico et al. reported that a patient with a missense mutation in the proline-rich domain of FGD1 showed typical clinical features as AAS.8) In this mutant FGD1, the serine residue at position 205 is replaced with isoleucine and the DH-PH modules necessary for the GEF activity remain intact.In our previous reports, we revealed that FGD1 and FGD3, a homologue of FGD1, underwent proteasomal degradation through the polyubiquitination by the ubiquitin ligase SCF FWD1 . 9,10) FGD1 and FGD3 share strikingly similar Dbl homology (DH) domains and adjacent pleckstrin homology (PH) domains, both of which (i.e., DH-PH modules) are responsible for guanine nucleotide exchange, however, there exist remarkable differences in their biological functions. 10)Whereas FGD1 induced long finger-like protrusions, FGD3 induced broad sheet-like protrusions when the level of GTPbound Cdc42 was significantly increased by the inducible expression of FGD3.10) Furthermore, FGD1 and FGD3 reciprocally regulated cell motility; when inducibly expressed in HeLa Tet-Off cells, FGD1 stimulated cell migrations whereas FGD3 inhibited it. 10)Although higher sequence similarity between FGD1 and FGD3 is observed in their DH-PH modules, there exist significant differences in their sequence in other regions; most prominently, FGD3 lacks the N-terminal proline-rich domain conserved in FGD1. Proline-rich sequences are k...

Myelin is dependent on the Charcot–Marie–Tooth Type 4H disease culprit protein FRABIN/FGD4 in Schwann cells

“…For example, the faciogenital dysplasia family member Fgd1, which is mutated in Aarskog–Scott syndrome, a rare X-linked disorder characterized by typical facial dysmorphism and skeletal and genital anomalies (Pasteris et al. , 1994), is involved in Cdc42-dependent processes, such as cell migration (Oshima et al. , 2011), vesicular transport (Egorov et al.…”

I’m coming to GEF you: Regulation of RhoGEFs during cell migration

“…154 There are some isolated examples of Cdc42-specific GEFs that regulate migration, which include bPix, Tuba, FGD1, FGD4, Ect2, and the Cdc42-specific DOCK proteins (DOCK6-11). 7,34,[158][159][160][161] However, most of these reports describe a specific situation, cell type, or a particular type of migration that has not been yet validated as a conserved mechanism.…”

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

“…Furthermore, two independent downstream CDC42 effectors, c-Jun N-terminal Kinase (JNK) and p70 S6 Kinase (S6K, also known as RPS6KB1), which are both involved in transcriptional regulation, become activated in FGD1-expressing cells (Olson et al, 1996). FGD1 also regulates persistent directional cell migration, and this function appears to involve the PRD domain (Oshima et al, 2011). In addition, expression of the DH and PH domains or the DH domain alone induces G1 cell cycle progression and entry into S phase as efficiently as constitutively active CDC42, suggesting that FGD1 facilitates G1 progression both through CDC42-dependent and CDC42-independent mechanisms (Nagata et al, 1998).…”

“…It could be inferred that the known point mutations impair FGD1 function directly or indirectly by altering catalytic activity, localisation and/or stability of the protein. For instance, whereas FGD1 stimulates directed cell migration, the FGD1 (S205I) mutant fails to do so (Oshima et al, 2011). Furthermore, the same mutation appears to confer increased stability to the protein (Hayakawa et al, 2005).…”

“…Activation of FGD1 leads to GDP/GTP exchange on CDC42, which, in turn, mediates a number of cellular events. Some of these events include cytoskeleton remodelling through the activation of JNK, which leads to cell migration (Olson et al, 1996;Oshima et al, 2011), the activation of ERK1/2 and subsequent focal adhesion kinase (FAK) activation, which leads to metastasis, or the activation of ERK1/2 and/or MLK3 and p38, which leads to osteoblast differentiation (Zou et al, 2011). FGD1 also regulates ECM remodelling through the formation of invadopodia in tumour cells or podosomes in endothelial cells (Daubon et al, 2011).…”